Intravenous magnesium sulfate for treating adults with...

Intravenous magnesium sulfate for treating adults with acute

asthma in the emergency department (Review)

Kew KM, Kirtchuk L, Michell CI

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2014, Issue 5

http://www.thecochranelibrary.com

Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

7BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

20DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 IV MgSO4 versus placebo, Outcome 1 Hospital admissions. . . . . . . . . . . 47

Analysis 1.2. Comparison 1 IV MgSO4 versus placebo, Outcome 2 Intensive care unit (ICU) admissions. . . . . 48

Analysis 1.3. Comparison 1 IV MgSO4 versus placebo, Outcome 3 High dependency unit (HDU) admissions. . . 48

Analysis 1.4. Comparison 1 IV MgSO4 versus placebo, Outcome 4 ED treatment duration (minutes). . . . . . 49

Analysis 1.5. Comparison 1 IV MgSO4 versus placebo, Outcome 5 Length of hospital stay (days). . . . . . . . 49

Analysis 1.6. Comparison 1 IV MgSO4 versus placebo, Outcome 6 Readmission. . . . . . . . . . . . . 50

Analysis 1.7. Comparison 1 IV MgSO4 versus placebo, Outcome 7 Heart rate (bpm). . . . . . . . . . . . 51

Analysis 1.8. Comparison 1 IV MgSO4 versus placebo, Outcome 8 Respiratory rate (breaths/min). . . . . . . 52

Analysis 1.9. Comparison 1 IV MgSO4 versus placebo, Outcome 9 Systolic blood pressure (mmHg). . . . . . . 53

Analysis 1.10. Comparison 1 IV MgSO4 versus placebo, Outcome 10 FEV1 (% predicted). . . . . . . . . . 54

Analysis 1.11. Comparison 1 IV MgSO4 versus placebo, Outcome 11 PEF (% predicted). . . . . . . . . . 55

Analysis 1.12. Comparison 1 IV MgSO4 versus placebo, Outcome 12 PEF (L/min). . . . . . . . . . . . 56

Analysis 1.13. Comparison 1 IV MgSO4 versus placebo, Outcome 13 Borg Dyspnoea Scale score. . . . . . . . 57

Analysis 2.1. Comparison 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses), Outcome 1 Hospital admissions

(by severity). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58


(by co-medications). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59


(risk of bias sensitivity). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61


(unpublished sensitivity). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Analysis 2.5. Comparison 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses), Outcome 5 PEF % predicted

(Goodacre change score sensitivity). . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 2.6. Comparison 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses), Outcome 6 PEF L/min

(Goodacre change score sensitivity). . . . . . . . . . . . . . . . . . . . . . . . . . . 64

64ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iIntravenous magnesium sulfate for treating adults with acute asthma in the emergency department (Review)


[Intervention Review]

Intravenous magnesium sulfate for treating adults with acuteasthma in the emergency department

Kayleigh M Kew1, Liza Kirtchuk1, Clare I Michell1

1Population Health Research Institute, St George’s, University of London, London, UK

Contact address: Kayleigh M Kew, Population Health Research Institute, St George’s, University of London, Cranmer Terrace, London,

SW17 0RE, UK. [email protected].

Editorial group: Cochrane Airways Group.

Publication status and date: New, published in Issue 5, 2014.

Review content assessed as up-to-date: 2 May 2014.

Citation: Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency

department. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD010909. DOI: 10.1002/14651858.CD010909.pub2.


A B S T R A C T

Background

Asthma is a chronic respiratory condition characterised by airways inflammation, constriction of airway smooth muscle and structural

alteration of the airways that is at least partially reversible. Exacerbations of asthma can be life threatening and place a significant burden

on healthcare services. Various guidelines have been published to inform management personnel in the acute setting; several include

the use of a single bolus of intravenous magnesium sulfate (IV MgSO4) in cases that do not respond to first-line treatment. However,

the effectiveness of this approach remains unclear, particularly in less severe cases.

Objectives

To assess the safety and efficacy of IV MgSO4 in adults treated for acute asthma in the emergency department.

Search methods

We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to 2 May 2014. We also searched

www.ClinicalTrials.gov and reference lists of other reviews, and we contacted trial authors to ask for additional information.

Selection criteria

We included randomised controlled trials (RCTs) of adults treated in the emergency department (ED) for exacerbations of asthma if

they compared any dose of IV MgSO4 with placebo.

Data collection and analysis

All review authors screened titles and abstracts for inclusion, and at least two review authors independently extracted study characteristics,

risk of bias and numerical data. Disagreements were resolved by consensus, and we contacted trial investigators to obtain missing

information.

We analysed dichotomous data as odds ratios using study participants as the unit of analysis, and we analysed continuous data as mean

differences or standardised mean differences using fixed-effect models. We rated all outcomes using GRADE and presented results in

Summary of findings table 1.

We carried out subgroup analyses on the primary outcome for baseline severity of exacerbations and whether or not ipratropium

bromide was given as a co-medication. Unpublished data and studies at high risk of bias for blinding were removed from the main

analysis in sensitivity analyses.

1Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department (Review)


mailto:[email protected]

Main results

Fourteen studies met the inclusion criteria, randomly assigning 2313 people with acute asthma to the comparisons of interest in this

review.

Most studies were double-blinded trials comparing a single infusion of 1.2 g or 2 g IV MgSO4 over 15 to 30 minutes versus a matching

placebo. Eleven were conducted at a single centre, and three were multi-centre trials. Participants in almost all of the studies had already

been given at least oxygen, nebulised short-acting beta2-agonists and IV corticosteroids in the ED; in some studies, investigators also

administered ipratropium bromide. Ten studies included only adults, and four included both adults and children; these were included

because the mean age of participants was over 18 years.

Intravenous MgSO4 reduced hospital admissions compared with placebo (odds ratio (OR) 0.75, 95% confidence interval (CI) 0.60

to 0.92; I2 = 28%, P value 0.18; n = 972; high-quality evidence). In absolute terms, this odds ratio translates into a reduction of

seven hospital admissions for every 100 adults treated with IV MgSO4 (95% CI two to 13 fewer). The test for subgroup differences

revealed no statistical heterogeneity between the three severity subgroups (I2 = 0%, P value 0.73) or between the four studies that

administered nebulised ipratropium bromide as a co-medication and those that did not (I2 = 0%, P value 0.82). Sensitivity analyses in

which unpublished data and studies at high risk for blinding were removed from the primary analysis did not change conclusions.

Within the secondary outcomes, high- and moderate-quality evidence across three spirometric indices suggests some improvement in

lung function with IV MgSO4. No difference was found between IV MgSO4and placebo for most of the non-spirometric secondary

outcomes, all of which were rated as low or moderate quality (intensive care admissions, ED treatment duration, length of hospital

stay, readmission, respiration rate, systolic blood pressure).

Adverse events were inconsistently reported and were not meta-analysed. The most commonly cited adverse events in the IV MgSO4

groups were flushing, fatigue, nausea and headache and hypotension (low blood pressure).

Authors’ conclusions

This review provides evidence that a single infusion of 1.2 g or 2 g IV MgSO4 over 15 to 30 minutes reduces hospital admissions

and improves lung function in adults with acute asthma who have not responded sufficiently to oxygen, nebulised short-acting beta2-

agonists and IV corticosteroids. Differences in the ways the trials were conducted made it difficult for the review authors to assess

whether severity of the exacerbation or additional co-medications altered the treatment effect of IV MgSO4. Limited evidence was

found for other measures of benefit and safety.

Studies conducted in these populations should clearly define baseline severity parameters and systematically record adverse events.

Studies recruiting participants with exacerbations of varying severity should consider subgrouping results on the basis of accepted

severity classifications.

P L A I N L A N G U A G E S U M M A R Y

Do magnesium sulfate infusions reduce the need for hospital admission in adults with acute asthma?

Why is this question important?

Asthma is a long-term condition that causes coughing, wheezing, shortness of breath and chest tightness. When symptoms significantly

worsen, often referred to as an attack or ’exacerbation,’ this can be life threatening. Management of exacerbations in the emergency

department (ED) varies, and some guidelines recommend the use of intravenous magnesium sulfate (IV MgSO4) when other treatments

have not helped. However, it is unclear whether IV MgSO4 is effective, particularly in less severe cases, and we wanted to answer this

question.

How did we answer the question?

We looked for trials that compared IV MgSO4 versus placebo in adults attending the ED with an asthma exacerbation. The most recent

searches were done on 2 May 2014. We were interested primarily in whether IV MgSO4 reduced the number of people needing to be

admitted to hospital, and we looked at several other measures as well, including time spent in the ED, lung function and symptom

scores.

What did we find?



Fourteen studies met the inclusion criteria, involving a total of 2313 people. These studies varied in terms of how bad exacerbations

had to be for people to be included and in terms of what other treatments were provided before IV MgSO4was given, but almost all

trials gave participants at least oxygen, nebulised short-acting medications and steroid tablets or injection.

Overall, IV MgSO4 reduced the need for hospital admission compared with placebo (seven fewer per 100 treated; 95% confidence

interval two to 13 fewer). Not enough information was available to show whether the reduction in hospital admissions was associated

with severity of the asthma exacerbation, or whether it made a difference what other treatments were given. Evidence suggests that IV

MgSO4 improved some lung function parameters, but for other measures such as heart rate, variation among study findings reduced

our confidence in the results. We did not find a difference between IV MgSO4 and placebo in most other measures (including time

spent in the ED, respiratory rate and blood pressure), and adverse events generally were poorly reported.

Conclusion

This review showed that IV MgSO4 reduces hospital admissions and improves lung function in adults with exacerbations of asthma

when other first-line medications have not relieved the acute symptoms (i.e. oxygen, inhaled short-acting medications and IV steroids).

Evidence for other measures of benefit and safety was limited.

Researchers should clearly define the severity of the asthma condition among people in their studies while carefully recording adverse

events.

This plain language summary is current as of May 2014.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

IV MgSO4 for treating adults with acute asthma in the ED

Patient or population: adults with acute asthma

Settings: emergency department

Intervention: IV MgSO4

Comparions: placebo

Both intervention and placebo groups received oxygen, short-acting beta2-agonists and oral or intravenous steroids before the infusion

Measurements were taken between 60 and 240 minutes after the start of the infusion

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No. of participants

(studies)

Quality of the evidence

(GRADE)

Assumed risk Corresponding risk

Control IV MgSO4

Hospital admissions 569 per 1000 498 per 1000

(442 to 549)

OR 0.75

(0.60 to 0.92)

1769

(11 studies)

⊕⊕⊕⊕high1,2

Intensive care unit (ICU) ad-

missions

14 per 1000 28 per 1000

(10 to 77)

OR 2.03

(0.7 to 5.89)

752

(1 study)

⊕⊕©©low3,4

Length of hospital stay (days) Mean length of hospital stay in

the control groups was

2.73 days5

Mean length of hospital stay in

the intervention groups was

0.03 days lower

(0.33 lower to 0.27 higher)

- 949

(3 studies)

⊕⊕©©low6,7,8

ED treatment duration (min-

utes)

Mean duration in the placebo

group was

228 minutes

Mean ED treatment duration in


4 minutes lower


- 96

(1 study)

⊕⊕©©low9,10,11

FEV1 (% predicted) Mean FEV1 in the placebo

group was

50% predicted

Mean FEV1 (% predicted) in


4.41 higher

(1.75 to 7.06 higher)

- 523

(4 studies)

⊕⊕⊕⊕high12,13,14

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PEF (L/min) Mean PEF in the placebo group

was

239 L/min

Mean PEF in the intervention

groups was

17.4 L/min higher

(8.64 to 26.17 higher)

- 1460

(8 studies)

⊕⊕⊕©moderate15,16,17

Respiratory rate (breaths/

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Mean respiration rate in the

placebo group was

20.7 respirations/min

Mean respiratory rate in the

intervention groups was

0.28 breaths/min lower


- 1195

(4 studies)

⊕⊕⊕©moderate18,19,20

*The basis for the assumed risk (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed

risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; ED: Emergency department; FEV1 : Forced expiratory volume in 1 second; ICU: Intensive care unit; IV: Intravenous; MgSO4: Magnesium sulfate; OR: Odds ratio; PEF:

Peak expiratory flow.

GRADE Working Group grades of evidence.

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1One study (Green 1992) introduced risk of bias, but the rest of the studies were generally well conducted.2I2 = 28%; P value 0.18; not statistically significant.3Confidence interval includes potential benefit and harm. Very few events and only 1 study (-2 for imprecision).4Only 1 study (Goodacre 2013) reported this outcome, but no other studies set out to measure it at the outset.5Weighted by sample size.6Two of the 3 studies were at high risk of bias for blinding, and there were some issues with selection bias.7I2 = 58%; P value 0.07, suggesting statistically significant heterogeneity.8Although only 3 studies reported this outcome, it was not named as an outcome in other studies.9Only 1 study (Green 1992), which was assessed as having high risk of bias for several domains.10Only 1 study (Green 1992), which had wide confidence intervals (-37.02 to 29.02).11Only 1 study reported ED treatment duration, but it was not named as an outcome in other studies.12Only 1 study (Bilaceroglu 2001) had the potential for risk of bias, but all other studies were low risk and included large numbers of

participants.13No significant heterogeneity was noted (I2 = 14%; P value 0.33).14Moderately wide confidence interval (1.75 to 7.06), but after discussion, review authors decided that no downgrade was required.

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of low risk and contributed most of the participant numbers.16Some heterogeneity between the studies, which was statistically significant (I² = 50%; P value 0.05). However, when random effects

were applied, conclusions were not changed.17Wide confidence intervals (8.64 to 26.17), but does not cross zero.18Very little heterogeneity observed between the studies (I² = 1%), which was not significant (P value 0.39).19Confidence interval (-0.77 to 0.20) includes significant benefit and potential harm (i.e. crosses the line of no effect).20Only 4 studies reported respiratory rate, but it was not named as an outcome in other studies.

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B A C K G R O U N D

Description of the condition

Asthma is a chronic respiratory condition characterised by airway

inflammation, constriction of airway smooth muscle and struc-

tural alteration of the airways that is at least partially reversible.

Common symptoms include cough, wheezing, difficulty breath-

ing, reduced exercise tolerance and chest tightness. Common trig-

gers include allergens, pollutants and viral infections, although

endogenous factors have also been identified. The World Health

Organization (WHO) recognises the global burden of asthma and

estimates a worldwide prevalence of 300 million people of all

ages, with 250,000 dying each year. Epidemiological data suggest

that prevalence is greatest in the developed world, with prevalence

amongst adults at 8.2% in the USA (CDC) and 9% to 10% in

the UK (DOH 2012).

Asthma can present with varying degrees of severity, and in the

most severe cases, it can cause daily chronic symptoms and frequent

exacerbations (defined as acute worsening of asthma symptoms).

Overarching principles of treatment focus on controlling daily

symptoms and preventing exacerbations through good education

and appropriate use of inhalers. Short-acting bronchodilators are

given to relieve bronchospasm, and corticosteroids for the underly-

ing inflammation; both are usually delivered via inhalers. Depend-

ing on the persistence of symptoms, inhalers can be taken regularly

(maintenance therapy) or on an as-needed basis (reliever therapy)

(BTS/SIGN 2012; GINA 2011). Treatment guidelines recom-

mend preventative management in the community and prompt

interventions during exacerbations to reduce mortality and other

negative outcomes (such as intubation and hospital admissions).

Description of the intervention

In severe exacerbations of asthma, which can be life threaten-

ing, most guidelines recommend the use of oxygen, nebulised or

intravenous beta2-agonists, nebulised antimuscarinics and intra-

venous or oral corticosteroids as first-line treatment (BTS/SIGN

2012; GINA 2011; NACA 2006; NAEPP 2007). Beta2-agonists

are recognised as most effective in relieving bronchospasm (Teoh

2012); however, anticholinergic inhalers have also been shown to

be effective in the treatment of acute asthma (Griffiths 2013).

When patients show poor response to these, or when they present

with a severe or life-threatening exacerbation, a single dose of in-

travenous (IV) or nebulised magnesium sulfate (MgSO4) can be

considered. Nebulised MgSO4 is the subject of a separate review

(Powell 2012). The recommended dosage of IV MgSO4 in the UK

is 1.2 g to 2 g, delivered by infusion over 20 minutes (BTS/SIGN

2012), but guidelines differ regarding how and when IV MgSO4

should be administered (Table 1),

National guidelines also vary with respect to definitions of asthma

severity and use of additional interventions. Table 1 offers a sum-

mary of treatment strategies recommended by some of these guide-

lines for the management of acute asthma.

How the intervention might work

Magnesium is an important intracellular and extracellular cation

that plays a key role in intracellular enzymatic reactions. Its mech-

anism of action in the context of an exacerbation of asthma is not

fully understood, but several theories have been proposed (Rowe

2013). It is believed to play a role in bronchial smooth muscle

relaxation via its ability to prevent calcium ion movement into

smooth muscle cells by blocking the voltage-dependent calcium

channels (Gourgoulianis 2001; Spivey 1990). Furthermore, some

evidence suggests that it may reduce the neutrophilic burst seen

with the inflammatory response (Cairns 1996), and that it may be

involved in acetylcholine release from cholinergic nerve terminals

and histamine release from mast cells (Dominguez 1998). The

combination of these properties contributes to relief of airflow ob-

struction and provides the theoretical basis for the effectiveness of

magnesium.

Why it is important to do this review

Acute asthma presentations represent a significant burden on

emergency departments (EDs) and carry a substantial mortality

risk, with 1143 deaths from asthma reported in the UK in 2010

(Asthma UK) and an estimated mortality rate of 1.1 deaths per

100,000 in the USA (CDC). In the UK, it is thought that “75%

of hospital admissions for asthma are avoidable and as many as

90% of the deaths from asthma are preventable” (Asthma UK).

The financial burden is also significant, with a cost to the National

Health Service (NHS) of £1 billion a year, 80% of which is spent

on the 20% of people with the most severe disease (DOH 2012).

Current guidelines advocate the use of IV MgSO4 in the treat-

ment of acute severe asthma, but evidence in the literature remains

inconclusive (Rowe 2009). New evidence from randomised con-

trolled trials published since the last version of this review may

alter the conclusions.

O B J E C T I V E S

To assess the safety and efficacy of IV MgSO4 in adults treated for

acute asthma in the emergency department.

M E T H O D S



Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of any follow-

up duration reported as full text, those published as abstract only

and unpublished data.

Types of participants

We included studies of adults (defined as over 18 years of age)

treated in the ED for acute asthma. If studies recruited both adults

and children, we contacted the study authors to try to obtain

separate data from adults.

Types of interventions

We included trials comparing any dose of IV MgSO4 versus

placebo. People with acute asthma often require multiple medica-

tions; therefore we included studies that allowed other treatments

(for maintenance, for exacerbation itself or for other co-morbidi-

ties), provided they were not part of the randomly assigned treat-

ment.

Types of outcome measures

Primary outcomes

• Hospital admissions.

Secondary outcomes

• ED treatment duration.

• Intensive care unit admissions.

• Vital signs (heart rate, respiratory rate, blood pressure,

oxygen saturation).

• Spirometry (peak expiratory flow (PEF), forced expiratory

volume within one second (FEV1)).

• Validated symptom scores.

• Adverse events.

Reporting in the trial of one or more of the outcomes listed here

was not an inclusion criterion for the review.

Search methods for identification of studies

Electronic searches

We identified trials from the Cochrane Airways Review Group

Specialised Register (CAGR), which is maintained by the Trials

Search Co-ordinator for the Group. The Register contains trial

reports identified through systematic searches of bibliographic

databases including the Cochrane Central Register of Controlled

Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED

and PsycINFO, and by handsearching of respiratory journals and

meeting abstracts (see Appendix 1 for further details). We searched

all records in the CAGR using the search strategy described in

Appendix 2.

We also

conducted a search of ClinicalTrials.gov (www.ClinicalTrials.gov)

and the WHO trials portal (www.who.int/ictrp/en/). We searched

all databases from their inception to the present, and we imposed

no restriction on language of publication.

Searching other resources

We checked reference lists of all relevant primary studies and review

articles for additional references. We also searched for errata or

retractions from included studies published in full text on PubMed

(www.ncbi.nlm.nih.gov/pubmed) and reported within the review

the date this was done.

Data collection and analysis

Selection of studies

Three review authors (KK, LK, CM) independently screened ti-

tles and abstracts for inclusion of all citations identified by the

search and coded them as ’retrieve’ (eligible or potentially eligible/

unclear) or ’do not retrieve.’ We retrieved the full-text study re-

ports/publications, and the review authors independently screened

the full-text documents and identified studies for inclusion. We

identified and recorded reasons for exclusion of ineligible studies.

We resolved disagreements through discussion, or, if required, we

consulted a fourth person. We identified and excluded duplicates

and collated multiple reports of the same study, so that each study

rather than each report was the unit of interest in the review. We

recorded the selection process in sufficient detail to complete a

PRISMA flow diagram and a Characteristics of excluded studies

table.

Data extraction and management

To record study characteristics and outcome data, we used a data

collection form that had been piloted on at least one study in the

review. All review authors (KK, LK, CM) extracted study char-

acteristics from included studies, and all review authors indepen-

dently extracted outcome data. We extracted the following study

characteristics.

• Methods: study design, duration of observation and follow-

up, details of any ’run-in’ period, number of study centres and

locations, withdrawals, dates of study.



• Participants: N, mean age, age range, gender, asthma

severity*, diagnostic criteria, co-morbidities, co-medications,

baseline lung function, inclusion and exclusion criteria.

• Interventions: intervention, dose, comparison, concomitant

and failed treatments, excluded medications.

• Outcomes: primary and secondary outcomes specified and

collected, time points reported.

• Notes: funding for trial, notable conflicts of interest of trial

authors.

We noted in the Characteristics of included studies table if out-

come data were not reported in a usable way. We resolved dis-

agreements by reaching consensus or by involving a fourth per-

son. One review author transferred data into the Review Manager

(RevMan) (version 5.2) file. We double-checked that data were

entered correctly by comparing data presented in the systematic

review versus data provided in the study reports. A second review

author (LK or CM) spot-checked study characteristics for accu-

racy against the trial report.

Assessment of risk of bias in included studies

All review authors independently assessed risk of bias for each

study using the criteria outlined in the Cochrane Handbook for

Systematic Reviews of Interventions (Higgins 2011), resolving dis-

agreements by discussion. We assessed the risk of bias according

to the following domains.

• Random sequence generation.

• Allocation concealment.

• Blinding of participants and personnel.

• Blinding of outcome assessment.

• Incomplete outcome data.

• Selective outcome reporting.

• Other bias.

We graded each potential source of bias as high, low or unclear and

provided a quote from the study report together with a justification

for our judgement in the Risk of bias in included studies table.

We summarised risk of bias judgements across different studies

for each of the domains listed. We considered blinding separately

for different key outcomes when necessary (e.g. for unblinded

outcome assessment, risk of bias for hospital admission may be

very different than for a patient-reported scale). When information

on risk of bias was related to unpublished data or correspondence

with a trial author, we noted this in the Risk of bias in included

studies table.

When considering treatment effects, we took into account the risk

of bias for all studies that contributed to that outcome.

Assessment of bias in conducting the systematic

review

We conducted the review according to this published protocol and

reported deviations from it in the Differences between protocol

and review section of the systematic review.

Measures of treatment effect

We analysed dichotomous data as odds ratios (ORs) and contin-

uous data as mean differences (MDs) or standardised mean dif-

ferences (SMDs) with 95% confidence intervals (CIs). If studies

reported several validated symptom measures, or if different scales

were reported across studies, we analysed the data as SMDs in one

analysis to reduce measurement error and to increase precision.

We entered data presented as a scale with a consistent direction of

effect. We narratively described skewed data reported as medians

and interquartile ranges.

We undertook meta-analyses only when this was meaningful (i.e.

when treatments, participants and the underlying clinical question

were similar enough for pooling to make sense).

When multiple trial arms were reported in a single trial, we in-

cluded only the relevant arms. When two relevant comparisons

from a single study were combined in the same meta-analysis, we

halved the control group to avoid double-counting.

Unit of analysis issues

For dichotomous outcomes, we used participants rather than

events as the unit of analysis (i.e. number of adults admitted to

hospital rather than number of admissions per adult).

Dealing with missing data

We contacted investigators or study sponsors to verify key study

characteristics and to obtain missing numerical outcome data

when possible (e.g. when a study was identified as abstract only).

When this was not possible, and when missing data were thought

to introduce serious bias, we conducted a sensitivity analysis to

explore the impact of including such studies in the overall assess-

ment of results.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials

in each analysis. When substantial heterogeneity was identified,

we explored possible causes by conducting prespecified subgroup

analyses.

Assessment of reporting biases

We created and examined a funnel plot to explore possible small-

study and publication biases. We considered the impact of unpub-

lished trials in the GRADE ratings for each outcome.

Data synthesis

We used a fixed-effect model and performed a sensitivity analysis

with random effects when significant heterogeneity was observed

(I² > 30%).



Summary of findings table

We created Summary of findings for the main comparison for

seven of the prespecified outcomes. We used the five GRADE

considerations (study limitations, consistency of effect, impre-

cision, indirectness and publication bias) to assess the quality

of a body of evidence as it relates to the studies that con-

tributed data to meta-analyses for the prespecified outcomes (http:

//www.gradeworkinggroup.org/). We applied methods and rec-

ommendations described in Section 8.5 and Chapter 12 of the

Cochrane Handbook for Systematic Reviews of Interventions (Higgins

2011) using GRADEpro software. We justified all decisions to

downgrade or upgrade the quality of studies by using footnotes,

and we made comments to aid readers’ understanding of the re-

view when necessary.

Subgroup analysis and investigation of heterogeneity

We carried out the following subgroup analyses for the primary

outcome, using the formal test for subgroup differences in Review

Manager (version 5.2) (Review Manager (RevMan)).

• Baseline severity (moderate, severe and life-threatening

exacerbations*).

• Mean age (≤ and > 65 years).

• Co-medications (with or without ipratropium bromide**).

*Since there is no single accepted metric for assessment of asthma

severity, we extracted baseline data relevant to the severity criteria,

as stated in the British Thoracic Society (BTS) guidelines (BTS/

SIGN 2012), that is,

• Clinical features (e.g. ability to complete sentences,

respiratory effort, conscious level, signs of exhaustion);

• Previous intensive care unit admissions;

• Pulse;

• Blood pressure;

• Respiratory rate;

• Pulse oximetry;

• Pulsed expiratory flow (PEF); and

• Arterial blood gas.

Exacerbations of the study populations were labelled as moderate,

severe or life threatening on the basis of available data, as judged by

an independent assessor who was not involved in the review pro-

cess and had no other details or results of the trials. Consistent with

British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines

Network (SIGN) criteria (BTS/SIGN 2012), for which the per-

centage predicted PEF was available, mean values less than 33%

were judged to be life threatening, 33% to 50% severe and over

50% moderate. When this measure was not available, or when

the value was close to a cutoff, other criteria were consulted, and

the value was then standardised across trials using studies report-

ing several indices. The decision to perform a subgroup analysis

by severity was informed by conclusions drawn in the previous

Cochrane review (Rowe 2009) that the intervention may be more

effective in cases of severe or life-threatening asthma.

**For co-medications, we grouped studies by whether investigators

gave ipratropium bromide in addition to other treatments (i.e.

short-acting beta2-agonists (SABAs) via a nebuliser or spacer, oral

or intravenous corticosteroids). Ipratropium bromide is included

in most guidelines, but it is unclear whether this treatment is

adopted in all EDs. Griffiths 2013 has demonstrated that it is an

effective adjunct to SABAs in children with asthma exacerbation

in the acute setting.

Sensitivity analysis

We plan to carry out the following sensitivity analyses.

• Studies at high risk of bias for blinding.

• Unpublished data.

Reaching conclusions

We have based our conclusions only on findings from the quan-

titative or narrative synthesis of included studies for this review.

We have avoided making recommendations for practice, and our

implications for research suggest priorities for future research and

outline remaining uncertainties in this area.

R E S U L T S

Description of studies

Full details of the conduct and characteristics of each included

study can be found in Characteristics of included studies, and rea-

sons for exclusion when full texts had to be viewed are given in

Characteristics of excluded studies.

Results of the search

119 references were identified by electronic searches, and 27 addi-

tional records were identified by a search of clinicaltrials.gov. Most

were excluded upon screening of titles and abstracts (n = 117).

Full texts were consulted for the remaining 29 references, and 10

were excluded at this stage, primarily because the study was not

conducted in an emergency setting (n = 7). Other reasons for ex-

clusion at this stage were ’study population did not have asthma’

(n = 2) and ’no placebo comparison’ (n = 1). Several unsuccessful

efforts were made to find a trial publication for one additional

study (Abd El Kader 1997), which is awaiting classification. The

remaining 18 citations related to 14 studies, which were included

in this review. Trial flow is presented in Figure 1.



http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009019.pub2/tables#CD009019-sec2-0020








Figure 1. Study flow diagram.



Included studies

Fourteen studies met the inclusion criteria, randomly assigning

2313 people with acute asthma to the comparisons of interest in

this review. Goodacre 2013 contributed the largest sample size to

the analyses, with 1109 participants randomly assigned to the two

intervention groups; in contrast, Del Castillo Rueda 1991 had

the smallest sample size, with 16 participants randomly assigned

to the intervention groups. Mean sample size across the included

studies was 165. Summary characteristics of the included trials are

presented in Table 2, and full details of each included study are

given in Characteristics of included studies.

Design and duration

Most of the studies included in this review were randomised,

double-blinded, placebo-controlled trials. Of those that were not,

two were randomised, single-blinded, placebo-controlled trials

(Bilaceroglu 2001; Singh 2008), one was unblinded with the con-

trol group receiving no placebo (Green 1992) and for two trials,

the study design was unclear from the information provided (Del

Castillo Rueda 1991; Matusiewicz 1994). For these two studies,

the former commented on randomisation but not blinding, and

the latter commented on neither randomisation nor blinding, al-

though both studies appeared to include treatment and control

groups.

The duration of the studies ranged from 45 minutes (Skobeloff

1989) to 260 minutes (Tiffany 1993). Most trials reported out-

come data at the end of study treatment periods, but further

follow-up provided in five studies ranged from six hours to one

month (Bijani 2001; Bilaceroglu 2001; Bloch 1995; Goodacre

2013; Silverman 2002). Most trials were conducted at a single

centre, occurring within one ED, except for Bloch 1995, which

was done across two EDs in the USA; Goodacre 2013, which took

place across 34 EDs in the UK and Silverman 2002, which was

completed across eight EDs in the USA.

Participant inclusion and exclusion criteria

All studies included participants with an exacerbation of asthma.

However differences between studies included the measures used

to define an exacerbation, with some using PEF and others using

FEV1, as well as the time at which these measurements were taken

(e.g. on arrival, after initial treatment).

PEF was used in seven studies (Bijani 2001; Bilaceroglu 2001;

Bradshaw 2007; Goodacre 2013; Matusiewicz 1994; Porter 2001;

Skobeloff 1989). Two studies (Bijani 2001; Skobeloff 1989) used

PEF < 200 L/min, Porter 2001 used PEF < 100 or < 25% predicted

and Matusiewicz 1994 specified PEF < 250 L/min or < 50% pre-

dicted as the cutoff to indicate an exacerbation. Both Bilaceroglu

2001 and Goodacre 2013 specified PEF < 50% predicted as a

cutoff. FEV1 was used as a criterion for inclusion in four stud-

ies (Bilaceroglu 2001; Bloch 1995; Silverman 2002; Singh 2008),

with the cutoff being FEV1 < 75% predicted (Bilaceroglu 2001;

Bloch 1995) or FEV1 < 30% (Silverman 2002; Skobeloff 1989).

Boonyavorakul 2000 used a severity score > 4 (Fischl Index, which

is a composite of vital signs, PEF and clinical features). Three stud-

ies (Del Castillo Rueda 1991; Green 1992; Tiffany 1993) did not

define the criteria used for an exacerbation.

Three studies did not define any exclusion criteria (Bijani 2001;

Del Castillo Rueda 1991; Matusiewicz 1994). For the remaining

studies (n = 11), exclusion criteria were quite consistent and in-

cluded diabetes mellitus, congestive cardiac disease, hypertension,

chronic renal failure, temperature > 38 ºC, pneumonia, pregnancy,

participants requiring ventilation and those who did not provide

consent.

Baseline characteristics of participants

The most common age range used across studies was 18 to 60

years (Silverman 2002; Singh 2008; Tiffany 1993). Bloch 1995

and Green 1992 used a range of 18 to 65 years, Porter 2001 18 to

55 years and Skobeloff 1989 18 to 60 years. Two studies (Bradshaw

2007; Goodacre 2013) included participants 16 years of age and

older, whilst Boonyavorakul 2000 included participants aged 15

to 65 years. Two studies included children and reported age ranges

of 12 to 85 years (Bijani 2001) and six to 65 years (Bilaceroglu

2001). From the studies for which we have only the abstract, Del

Castillo Rueda 1991 did not specify the age of participants, and

Matusiewicz 1994 described participants as ’adults.’

Most of the studies were well matched between control and inter-

vention with respect to sex (other than Porter 2001, in which the

IV MgSO4arm consisted of 50% men compared with 25% in the

placebo arm).

Only four studies reported ethnicity data (Bilaceroglu 2001;

Goodacre 2013; Green 1992; Silverman 2002). The percent-

age classified as ’white’ ranged from 59% to 100% in three of

these (Bilaceroglu 2001; Goodacre 2013; Green 1992), whereas

Silverman 2002 had a greater preponderance of black and His-

panic participants, with only 11% to 14% of participants classi-

fied as ’white.’

Five studies distinguished smokers (Bilaceroglu 2001; Bloch 1995;

Goodacre 2013; Silverman 2002; Singh 2008), and in all cases

the placebo and intervention arms were well matched. The per-

centage of current smokers within these studies ranged from 7%

to 10% in Singh 2008, to 30% to 35% in Goodacre 2013 and

Silverman 2002. The remainder of the studies (Bilaceroglu 2001;

Bloch 1995) combined current smokers and ex-smokers, and their

proportions ranged from 29% to 50%.



Three studies further stratified participants by severity of asthma

using American (Bilaceroglu 2001; Bloch 1995) and British

(Bradshaw 2007) Thoracic Society Guidelines.

As stated in the protocol, we categorised study populations on the

basis of average severity to conduct a subgroup analysis. Judge-

ments of severity were based on baseline severity characteristics

presented in the trials, which are summarised in Table 3. The justi-

fication for each judgement is given in each study’s characteristics

table.

Characteristics of the interventions

IV MgSO4

In nine studies a dose of 2 g IV was used, usually in 50 to 100 mL

(250 mL in Singh 2008) of 0.9% normal saline or 5% dextrose

solution, and was infused over periods ranging from 15 to 30

minutes.

Bradshaw 2007, Del Castillo Rueda 1991, Matusiewicz 1994 and

Skobeloff 1989 used a dose of 1.2 g IV MgSO4 in solutions akin

to those mentioned above. Bijani 2001 used doses calculated by

weight of 25 mg/kg; this reflects the broader age range of the

participants.

Placebo group

All studies had a placebo arm except Green 1992, in which no

placebo was administered to the control group. In all other cases,

the same solution that was used to infuse IV MgSO4 to the treat-

ment group was used as the control solution, in equal volume

and over the same time period. Boonyavorakul 2000 added 2 mL

sterile water to the control solution, and Silverman 2002 does not

comment on the specific solution used for control but describes it

as ’like appearing solution’ of equal volume.

Co-medications

A number of other drugs commonly used in acute asthma were

co-administered, and there was a degree of variation in the way

this was done. In all trials participants received nebulised SABA

(salbutamol and, in one case, metaproterenol sulfate), and most

also described the use of oxygen (n = 10) and IV corticosteroids

(n = 10) before IV MgSO4 was given.

Goodacre 2013 administered oral prednisolone rather than IV

corticosteroids, and the form of corticosteroid administered was

unclear in Bijani 2001, Del Castillo Rueda 1991 and Bilaceroglu

2001. In the latter, the decision to administer was based on the

severity category to which the participant had been assigned.

Use of oxygen was described in 10 studies, although some study

authors commented that this was the case only if clinically indi-

cated (Bilaceroglu 2001; Boonyavorakul 2000). Some authors did

not describe the use of oxygen, although they may not have con-

sidered this to be a drug treatment requiring mention in the treat-

ment protocol (Bloch 1995; Del Castillo Rueda 1991; Skobeloff

1989; Tiffany 1993).

Three studies administered aminophylline or theophylline (Bijani

2001; Skobeloff 1989; Tiffany 1993), and in Skobeloff 1989, this

was guided by serum theophylline levels.

Nebulised ipratropium bromide was administered in four stud-

ies (Bradshaw 2007; Goodacre 2013; Matusiewicz 1994; Singh

2008). Goodacre 2013 and Green 1992 commented that other in-

terventions were permitted at the discretion of the treating physi-

cian, although they did not specify which ones were permitted.

Outcomes and analysis structure

Most studies reported the number of participants who required

hospitalisation after treatment (n = 11), but secondary outcomes

were inconsistently reported. Three studies reported length of hos-

pital stay for those hospitalised, and only one study at high risk of

bias reported the duration of ED treatment (Green 1992). Read-

mission was reported in Bloch 1995 and Goodacre 2013 after a

week and a month, respectively.

Lung function was reported in most of the studies, although this

was done in different ways (primarily percentage predicted FEV1

and PEF, and PEF in litres per minute). Absolute values or changes

in FEV1 (L) were not consistently reported. Bloch 1995 did not

report standard deviation for FEV1, but the study was included

on the basis of variance derived from the P value reported in the

paper. This resulted in an unusually large standard deviation but

did not significantly change the final results.

In the PEF analysis, we combined three studies reporting mean

change from baseline (Bijani 2001; Skobeloff 1989; Tiffany 1993)

with five reporting absolute endpoint scores (Goodacre 2013;

Green 1992; Matusiewicz 1994; Porter 2001; Silverman 2002).

Four studies reported heart rate, respiratory rate and systolic blood

pressure (Bloch 1995; Goodacre 2013; Silverman 2002; Singh

2008). Bijani 2001 reported respiratory rate, but the data could

not be included because no measure of variance was provided.

Goodacre 2013 reported oxygen saturation for participants on and

off oxygen separately, but because no other studies reported data,

we did not perform a meta-analysis. Partial pressure was reported

in one study (Bilaceroglu 2001), but again this was not formally

analysed. These results are summarised narratively.

Validated symptom scales generally were not reported in the stud-

ies, but four studies reported scores on the Borg Dyspnoea Scale

(Bloch 1995; Porter 2001; Silverman 2002; Singh 2008). One

additional study (Goodacre 2013) measured breathlessness using

a visual analogue scale (VAS), which we chose not to analyse, as

it was not validated. Boonyavorakul 2000 used the Fischl Index,

which is a composite of vital signs, PEF and clinical features. As

individual measures were not available, the data were not analysed.

A large degree of disparity was noted in the reporting of adverse



events; this precluded pooling of data in the meta-analysis. Five

studies reported no information on adverse events (Bijani 2001;

Del Castillo Rueda 1991; Matusiewicz 1994; Silverman 2002;

Tiffany 1993), although Silverman 2002 noted that no major ad-

verse events were reported. Boonyavorakul 2000 and Green 1992

described minor adverse events such as flushing and fatigue, but

these were not quantified. Other studies quantified adverse events

for the duration of the treatment period, which ranged from 60 to

240 minutes. As such, we summarised information across studies

narratively in the results.

Subgroup and sensitivity analyses

We conducted subgroup analyses on the primary outcome (hospi-

tal admissions) for baseline severity and co-medications. For sever-

ity, 15 groups were identified across the 11 studies reporting the

outcome: two moderate, six severe and seven life threatening.

We performed the analysis based on whether ipratropium bromide

was administered as described in the protocol. Bradshaw 2007,

Goodacre 2013, Matusiewicz 1994 and Singh 2008 were the only

studies in which ipratropium bromide was given; three of these

are UK studies. However, as information about co-medications

was inconsistently reported (summarised above and in Table 2),

and it was often unclear when infusions or nebulisers were given,

we were conservative in interpretation and have summarised the

limitations of the analysis in the discussion. We could not carry

out a subgroup analysis based on mean age (≤ and > 65 years), as

no trials solely recruited older adults.

We also conducted two sensitivity analyses excluding trials at high

risk of bias for blinding and those that contributed only unpub-

lished data. Bilaceroglu 2001, Green 1992 and Matusiewicz 1994

were removed from the prior, and only Matusiewicz 1994 from

the latter. No full paper was available for Del Castillo Rueda 1991,

but this study did not report hospital admissions, and although

only an abstract was available in English for Bilaceroglu 2001, the

full paper had been published in Turkish, from which we were

able to obtain further information. None of the studies provided

additional unpublished data for the primary outcome.

We added a post-hoc sensitivity analysis using change from base-

line instead of endpoint means from Goodacre 2013, as baseline

imbalances were noted in this study.

Excluded studies

Studies that took place outside of an acute setting were excluded,

as were those concerned with the effects of nebulised magnesium

sulfate (the subject of another review (Powell 2012)).

We excluded trials that were exclusively concerned with children,

defined as those younger than 18 years of age. These studies will be

dealt with in a separate Cochrane review (Griffiths 2014). We in-

cluded studies in which participants were both older and younger

than 18. Bradshaw 2007 and Goodacre 2013 included partici-

pants 16 years of age and older, and we believe that these data

are applicable to adults, as we would not expect significant phys-

iological differences between the ages of 16 and 18. Bijani 2001,

Boonyavorakul 2000 and Bilaceroglu 2001 included participants

12 to 85 years and 15 to 65 years of age, respectively; we endeav-

oured to obtain data for adults only but were ultimately unsuc-

cessful. Age ranges were unclear in three studies, although the im-

plication was that participants were adults (Bilaceroglu 2001; Del

Castillo Rueda 1991; Matusiewicz 1994).

Risk of bias in included studies

For details of the risk of bias rating for each study and the reasons

for each rating, see Characteristics of included studies. A sum-

mary of risk of bias judgements by study and domain (alloca-

tion generation, allocation concealment, blinding and incomplete

data) can be found in Figure 2.







Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Allocation

We assessed six studies to be at low risk of bias for random sequence

generation and seven for allocation concealment. Both Bloch 1995

and Bradshaw 2007 used random number generation by phar-

macy, with blinding of physicians to the allocation. Goodacre 2013

used telephone- or Internet-generated randomisation sequencing,

whilst Porter 2001 used a random number generator producing

a code, and in both studies, numbered treatment packs were pre-

pared in pharmacy before they were used by physicians. Silverman

2002 used 1:1 randomisation tables, and the pharmacy prepared

vials of placebo or IV MgSO4 with identical appearances and la-

belled with study IDs. Singh 2008 used 1:1 randomisation tables,

and study numbers were concealed in envelopes until allocation

was completed.

Skobeloff 1989 did not provide sufficient details of random se-

quence allocation to warrant a low risk bias judgement but ade-

quately described allocation concealment.

Two studies (Boonyavorakul 2000; Tiffany 1993) detailed ad-

equate randomisation processes (computer-generated lists); in

Tiffany 1993, this was managed by pharmacy, but no information

about allocation concealment was provided, and hence this study

was assessed to be at unclear risk in this domain.

Bilaceroglu 2001, Del Castillo Rueda 1991 and Bijani 2001 com-

mented on randomisation, although no further details were pro-

vided and no comment on allocation concealment was made;

hence these studies were assessed as unclear in both areas. The

same assessment was made with Matusiewicz 1994, for which no

information about randomisation or allocation concealment was

provided.

We considered Green 1992 to be at high risk of bias in these

domains, as participants were allocated to control or treatment

group according to the day of presentation to the department.

Blinding

In the domains of both performance and detection bias, we con-

sidered most (n = 8) of the included studies to be at low risk of bias

(Bloch 1995; Boonyavorakul 2000; Bradshaw 2007; Goodacre

2013; Porter 2001; Silverman 2002; Skobeloff 1989; Tiffany

1993). These were described as double-blinded placebo-controlled

trials, and investigators provided adequate detail about who was

blinded and commented that their primary outcomes were non-

subjective assessor-rated outcomes.

Singh 2008 described this study as single-blinded; however

through correspondence with the study author, we were able to

ascertain that participants and assessors of spirometric and clin-

ical outcomes were blinded, as was the chief resident who made

the decision about admission. The individual administering the

medication was unblinded; therefore we rated performance bias

as ’unclear’ and detection bias as ’low risk.’

We believe that although Bijani 2001 performed a double-blinded

study with decoding done at completion of the study, limited

detail was provided about who the blinded parties were, and we

considered this to be unclear.

We have no information for these domains from Del Castillo

Rueda 1991 and Matusiewicz 1994 and have graded them as also

having unclear risk of bias.

We assessed that both Bilaceroglu 2001 and Green 1992 are at

high risk of bias in these domains. The former study was single-

blinded, and further correspondence with the study author con-

firmed that only participants were blinded to treatment, allowing

for bias in assessment of outcome measures. In Green 1992, the

physicians were unblinded to randomisation, and although nei-

ther participants nor respiratory therapists carrying out PEF mea-

sures were aware that a study was being conducted, they may have

been aware of the treatment received.

Incomplete outcome data

We considered that in half of the included studies (n = 7), the risk

of attrition bias was low, and in the other half, the risk was unclear.

In studies for which we considered the risk to be low (Bilaceroglu

2001; Bloch 1995; Boonyavorakul 2000; Bradshaw 2007;

Goodacre 2013; Singh 2008; Skobeloff 1989), withdrawal rates

were clearly documented and numbers were low, with similar rates

reported in placebo and control groups.

In four studies (Bijani 2001; Del Castillo Rueda 1991;

Matusiewicz 1994; Tiffany 1993), no information was provided

about withdrawal rates, hence the reason for considering the risk

to be unclear.

In Green 1992, 97 of 217 participants were excluded from anal-

ysis, with 80 participants repeat attenders (no comment on the

groups to which they had been randomly assigned) and the med-

ical records of 17 participants misplaced. No comment was made

about whether there was intention to treat any of the participants

who withdrew, although at the point of analysis, numbers in all

groups were similar.

Porter 2001 reports that where repeat attendance to the depart-

ment was documented, data from only the first presentation were

used, but no further commentary was made about withdrawals.

Silverman 2002 provides a very detailed report of participants with

protocol violations who were retained in the intention-to-treat

data set and gives reasons for these inclusions. However, attrition

rates were quite high and were not provided for each arm. As such

it was unclear whether attrition was balanced between groups, and

the study was rated as ’unclear.’



Selective reporting

We considered that only five studies demonstrated low risk of bias

in reporting of outcome data: Bijani 2001; Bloch 1995; Goodacre

2013; Silverman 2002; and Singh 2008. Although Bijani 2001 did

not report on arterial blood gas (ABG) results as was planned, other

data were well reported, and we believe that the ABG measure was

not critical to the study. Both Goodacre 2013 and Singh 2008

provided further raw data when directly contacted by the review

authors, and this completed the outcomes planned for assessment.

The published report of Bloch 1995 provided data at only one of

the prespecified time points and FEV1 was provided graphically,

but the study author provided additional data to the review authors

upon request.

We considered the following studies to be unclear for risk of re-

porting bias: Bilaceroglu 2001; Del Castillo Rueda 1991; Green

1992; Matusiewicz 1994; and Porter 2001. We have only the ab-

stract for both Del Castillo Rueda 1991 and Matusiewicz 1994;

The former provided no outcome data, just a written description

of investigator conclusions, and the latter provided outcomes at

only one of the recorded time points. Bilaceroglu 2001 did pro-

vide further raw data to the review authors on request, but this

still did not include all time points laid out in the methodology.

Green 1992 provided outcome data, but the methodology did not

indicate the primary outcome measures selected when the study

was designed. Porter 2001 provided all primary outcome data at

the prespecified time point; however data were also collected at

other time points, and this was not reported.

We considered that four studies demonstrated high risk of re-

porting bias. Boonyavorakul 2000 provided only raw admission

data, and severity scores were provided only in terms of ’variance.’

Bradshaw 2007, Skobeloff 1989 and Tiffany 1993 provided raw

data for only a subset of outcomes or time points, with remaining

results presented graphically or without variance and with no re-

porting of raw data.

Other potential sources of bias

No additional sources of bias were identified.

Effects of interventions

See: Summary of findings for the main comparison IV MgSO4for treating adults with acute asthma in the emergency department

Primary outcomes

Hospital admissions

Combining 11 studies (n = 972) revealed a significant reduction

in hospital admissions compared with placebo (OR 0.75, 95%

CI 0.60 to 0.92; high-quality evidence; Analysis 1.1). Some het-

erogeneity that was not statistically significant was observed (I2 =

28%; P value 0.18). In absolute terms, this odds ratio translates to

a reduction of seven hospital admissions for every 100 adults (95%

CI two to 13 fewer) treated with IV MgSO4 (Figure 3). There was

no reason to downgrade for any of the five domains in GRADE

(risk of bias, inconsistency, indirectness, imprecision, publication

bias). Specifically, risk of bias was generally low or unclear across

trials, heterogeneity was not significant, trials matched the research

question well, confidence intervals were relatively narrow and al-

most all studies contributed data to the analysis.



Figure 3. In the control group, 57 of 100 people were admitted to hospital, compared with 50 (95% CI 45 to

55) of 100 for the IV MgSO4 group.

Secondary outcomes

Intensive care admissions

Evidence from one study (Goodacre 2013; n = 752) showed no

significant difference in admission rates between IV MgSO4 and

placebo (OR 2.03, 95% CI 0.70 to 5.89; moderate-quality ev-

idence; Analysis 1.2). The same study reported the number of

participants admitted to the high dependency unit and showed

no significant difference between the two arms (OR 1.05, 95%

CI 0.57 to 1.94; moderate-quality evidence; Analysis 1.3). Both

outcomes contained few events from only one study, so they were

downgraded twice for imprecision, and the quality of evidence was

rated as ’low.’

ED treatment duration

Only one study (Green 1992; n = 452) reported ED treatment

duration and found no significant difference between IV MgSO4

and placebo (MD -4.00, 95% CI -37.02 to 29.02; low-quality

evidence; Analysis 1.4). The outcome was downgraded for risk of

bias and imprecision.

Length of hospital stay (days)

Combining three studies reporting the outcome (n = 949) revealed

no significant difference in time spent in hospital between the IV

MgSO4 and placebo groups (MD -0.03, 95% CI -0.33 to 0.27;

low-quality evidence; Analysis 1.5). The evidence was downgraded

for risk of bias and inconsistency (I2 = 53%; P value 0.10). As

I2 was over the 30% defined in the protocol, we performed a

sensitivity analysis using random effects, which did not change the

conclusions (MD -0.16, 95% CI -0.68 to 0.37).

Readmission



Too few events were described in only two studies to indicate

whether IV MgSO4 had an effect on readmission to hospital com-

pared with placebo (OR 2.30, 95% CI 0.66 to 7.99; moderate-

quality evidence; Analysis 1.6). No statistical heterogeneity was

noted between the studies (I2 = 0%; P value 0.34), but the out-

come was downgraded for imprecision.

Vital signs

Heart rate

Combining four studies (n = 1195) showed a small significant

reduction in heart rate with IV MgSO4 compared with placebo

(MD -2.37, 95% CI -4.13 to -0.61; moderate-quality evidence;

Analysis 1.7). However a high degree of heterogeneity was ob-

served, which was statistically significant and warranted down-

grading (I2 = 78%; P value 0.004). A sensitivity analysis using

random effects decreased precision significantly, with confidence

intervals including both significant benefit and potential harm of

IV MgSO4 (MD -2.61, 95% CI -6.58 to 1.35).

Respiratory rate

When five studies were combined (n = 1276), IV MgSO4 did

not show a significant reduction in respiratory rate compared with

placebo (MD -0.28, 95% CI -0.77 to 0.20; moderate-quality ev-

idence; Analysis 1.8). Heterogeneity was not significant (I2 = 1%;

P value 0.39), but the evidence was downgraded for imprecision

because confidence intervals included significant benefit and po-

tential harm of the treatment.

Systolic blood pressure

Four studies (Bloch 1995; Bradshaw 2007; Goodacre 2013;

Silverman 2002; n = 1264) reporting systolic blood pressure

showed no difference between IV MgSO4 and placebo (MD 0.08,

95% CI -1.89 to 2.05; moderate-quality evidence; Analysis 1.9).

Heterogeneity was high, and although it was not statistically sig-

nificant, authors considered it large enough to warrant downgrad-

ing for inconsistency (I2 = 51%; P value 0.11). A sensitivity anal-

ysis using random effects did not change the conclusions (MD -

0.73, 95% CI -4.13 to 2.67).

Oxygen saturations

One study reported outcomes separately for those receiving and

those not receiving oxygen (Goodacre 2013). This outcome was

not reported in other studies; therefore we were unable to meta-

analyse the data.

Spirometry

FEV1 (% predicted)

When four studies were combined (Bilaceroglu 2001; Bloch 1995;

Silverman 2002; Singh 2008) (n = 523), significant improvement

in percentage predicted FEV1 was seen in the IV MgSO4 group

compared with the placebo group (MD 4.41, 95% CI 1.75 to 7.06;

high-quality evidence; Analysis 1.10). No significant heterogeneity

was noted among studies (I2= 14%; P value 0.33).

During data analysis, reported standard deviations in Bilaceroglu

2001 were outliers and appeared to be more consistent with stan-

dard error values; the author confirmed that this was the case. In

addition, Bloch 1995 reported no standard deviations; therefore

the standard error of the mean was calculated from the graphs.

PEF (% predicted)

Three studies (Bradshaw 2007; Goodacre 2013; Silverman 2002;

n = 1129) reported PEF (% predicted) and showed a statistically

significant improvement in PEF with IV MgSO4 compared with

placebo (MD 4.78, 95% CI 2.14 to 7.43; high-quality evidence;

Analysis 1.11). Heterogeneity between studies was high but was

not statistically significant (I2 = 45%; P value 0.16), so the evidence

was not downgraded. A sensitivity analysis with random effects

did not change our conclusions (MD 5.17, 95% CI 1.15 to 9.19).

On the basis of observed baseline imbalances in the largest study

(Goodacre 2013), a second sensitivity analysis using change from

baseline instead of endpoint means substantially reduced the effect

(MD 1.57, 95% CI -0.55 to 3.69; I2 = 79%, P = 0.009; Analysis

2.5).

PEF (L/min)

Combining eight studies (n = 1460) revealed that IV MgSO4 im-

proved PEF compared with placebo (MD 17.40, 95% CI 8.64 to

26.17; moderate-quality evidence; Analysis 1.12). However sta-

tistically significant heterogeneity between the studies (I2 = 50%;

P value 0.05) warranted downgrading. A sensitivity analysis with

random effects did not change our conclusions (MD 18.35, 95%

CI 4.12 to 32.58). As with the percentage PEF predicted analysis,

a second sensitivity analysis using Goodacre 2013 change from

baseline substantially reduced the magnitude of effect (MD 9.44,

95% CI 2.07 to 16.81; I2 = 68%, P = 0.003; Analysis 2.6).

Validated symptom scores

Five studies used symptom scales, all measuring breathlessness (n =

1237). The Borg Dyspnoea Scale was used by four studies (Bloch

1995; Porter 2001; Silverman 2002; Singh 2008), and Goodacre

2013 used a VAS for breathlessness. Data for the Borg Dyspnoea

Scale revealed no significant change with IV MgSO4 compared



with placebo (MD -0.22, 95% CI -0.55 to 0.12; high-quality

evidence; Analysis 1.13), and no significant heterogeneity between

studies was noted (I2 = 0%; P value 0.82).

Similarly, Goodacre 2013 reported no significant change in VAS

score with IV MgSO4 compared with placebo (MD -3.00, 95%

CI -7.09 to 1.09).

Adverse events

The most commonly cited adverse events were flushing, fatigue,

nausea and headache; some study authors also commented on

hypotension.

Bilaceroglu 2001 reported flushing in 42% of those receiving IV

MgSO4 versus no flushing in the placebo group. Although paraes-

thesia, vertigo and hypotension were also reported, no marked dif-

ferences between treatment and placebo arms were observed.

Bloch 1995 reported that 58% of those receiving IV MgSO4 re-

ported adverse events, including the sensation of flushing, fatigue

and burning at the IV site, with one participant experiencing tran-

sient urticaria in the upper extremities.

Bradshaw 2007 reported minor adverse events in 8% of those

receiving IV MgSO4 (headache, flushing, dizziness), with only one

participant in the placebo arm reporting flushing (1.5%).

Goodacre 2013 reported the rate of adverse events (death, arrhyth-

mia, cardiac arrest, non-invasive ventilation, intubation, other) as

13% in the treatment group compared with 10% in the placebo

group, although these rates fall almost entirely in the ’other’ cate-

gory. One death of an unspecified cause (1%) was reported in the

IV MgSO4 group compared with none in the placebo group. No

other trials reported deaths. Goodacre 2013 reported commonly

cited adverse events as a separate category and revealed a statisti-

cally significant increase in adverse events in the IV MgSO4 group

(OR 1.68, 95% CI 1.07 to 2.63; P value 0.025).

Both Porter 2001 and Singh 2008 reported that the difference

between rates of adverse events (including deep tendon reflexes)

among participants given IV MgSO4 versus placebo was not sta-

tistically significant.

Skobeloff 1989 reported higher rates of fatigue (32% vs 11%),

warmth (26%) and lightheadedness (5%) in the IV MgSO4 group,

but the numbers in this study were small.

With respect to blood pressure, Bilaceroglu 2001 reported hy-

potension in 5% versus 3% of participants in the treatment versus

placebo groups, whilst Goodacre 2013 reported 8% versus 6%,

respectively. Bradshaw 2007 reported a non-significant trend for

decreasing blood pressure at 60 minutes, and Singh 2008 reported

no hypotension.

Subgroup analyses

Baseline severity (moderate, severe and life-threatening

exacerbations)

The test for subgroup differences revealed no statistical hetero-

geneity between the three severity subgroups (I2 = 0%; P value

0.73), and between-trial heterogeneity was significant within all

three subgroups (I2 = 50%; P value 0.01).

Mean age (≤ and > 65 years)

Most studies included participants over age 65, but all population

mean ages were much lower than the cutoff. As we did not have

access to individual participant data within the trials, we were

unable to draw any conclusions regarding potential differential

effects of IV MgSO4 due to age.

Co-medications (with and without nebulised ipratropium

bromide)

The test for subgroup differences showed no significant differences

between the four studies that administered nebulised ipratropium

bromide as a co-medication and those that did not (I2 = 0%; P

value 0.82). Between-trial heterogeneity was not statistically sig-

nificant within either of the two subgroups (I2 = 28%; P value

0.18).

Sensitivity analysis

Studies at high risk of bias for blinding

When three studies that were given a ’high’ or ’unclear’ rat-

ing for blinding were removed (Bilaceroglu 2001; Green 1992;

Matusiewicz 1994), the pooled effect for hospital admissions was

slightly larger in favour of IV MgSO4 (OR 0.72, 95% CI 0.57 to

0.91; Analysis 2.3). Heterogeneity was slightly larger than in the

main analysis, but this difference was not statistically significant

(I2 = 35%; P value 0.15).

Unpublished data

Of the two studies for which only a conference abstract was avail-

able, one reported hospital admissions (Matusiewicz 1994). When

this study was removed from the primary outcome, the magnitude

of the effect in favour of IV MgSO4 was slightly increased (OR

0.73, 95% CI 0.58 to 0.91), but this did not change the conclu-

sions. Some heterogeneity that was not significant was reported (I2 = 32%; P value 0.15).

D I S C U S S I O N

Summary of main results



Fourteen studies met the inclusion criteria, randomly assigning

2313 people with acute asthma to the comparisons of interest in

this review. A recent large study (Goodacre 2013) accounted for a

large proportion of the total number of participants (n = 752).

The included studies were mostly randomised, double-blinded

trials comparing 1.2 g or 2 g IV MgSO4 versus a matching placebo

infusion. All of these studies included participants who had an

exacerbation of asthma, although definitions and inclusion criteria

varied. Ten studies included only adults; four included adults and

children and were included because the mean age was over 18 years.

Inclusion criteria varied, and studies assigned a level of severity

to participants, which we then verified against BTS/SIGN 2012

criteria, confirming that all studies included exacerbations of at

least moderate severity.

Eleven studies could be included in the primary analysis and

showed that IV MgSO4 reduced hospital admissions compared

with placebo (OR 0.75, 95% CI 0.60 to 0.92; I2 = 28%; P value

0.18; n = 972; high-quality evidence). In absolute terms, this odds

ratio translates into a reduction of seven hospital admissions for

every 100 adults (95% CI two to 13 fewer) treated with IV MgSO4

(Figure 3). The test for subgroup differences did not reveal sta-

tistical heterogeneity between the three severity subgroups (I2 =

0%; P value 0.73), or between the four studies that administered

nebulised ipratropium bromide as a co-medication and those that

did not (I2 = 0%;, P value 0.82). Sensitivity analyses removing

unpublished data and studies at high risk for blinding from the

primary analysis did not change conclusions; this increased our

confidence in the effect.

Within the secondary outcomes, evidence of high and moderate

quality across three spirometric indices suggested some improve-

ment in lung function with IV MgSO4; however the clinical sig-

nificance of the size of these effects is uncertain, and baseline im-

balances in the largest study reduced our confidence in some of

the findings. Although close, the mean difference in PEF (L/min)

found in this meta-analysis did not reach the minimal clinically

important difference (MCID) defined by Santanello 1999 (18.79

L/min). There are no accepted MCIDs for the percentage pre-

dicted measures reported in most of the trials. Mean FEV1 in litres,

for which an MCID does exist, was reported in only two of the

14 trials.

No difference between IV MgSO4 and placebo was found for

most of the non-spirometric secondary outcomes, all of which

were rated of low or moderate quality (intensive care admissions,

ED treatment duration, length of hospital stay, readmission, res-

piration rate, systolic blood pressure).

Adverse events were inconsistently reported and were not meta-

analysed. The most commonly cited adverse events in the IV

MgSO4 groups were flushing, fatigue, nausea and headache and

hypotension. However we found no significant difference in blood

pressure between the IV MgSO4 and placebo groups.

Overall completeness and applicability ofevidence

A large degree of variation between prescribing procedures was

evident in the trials, but doses used in the included studies are in

accord with current BTS/SIGN 2012, GINA 2011 and NACA

2006 guidelines. However, the treatment protocols differed as to

when the decision to administer IV MgSO4 was made; the dosage,

frequency and form of co-medications and the order in which

the medications were administered in relation to one another. We

suspect that differences between individual EDs both within and

among countries were significant, and insufficient reporting in the

trials themselves further complicated interpretation of the sub-

group analysis for co-medications. As such, although no evidence

suggested a difference in the efficacy of IV MgSO4 delivered in

settings where ipratropium bromide was prescribed, we cannot

exclude the possibility that other combinations of co-medications

may significantly alter the effectiveness of IV MgSO4. Moreover,

as almost all of the studies administered short-acting beta2-ago-

nists, oxygen and IV corticosteroids before MgSO4, the evidence

is suitably applied to situations for which these medications have

already been prescribed. Doses of magnesium used and method

and rate of delivery were relatively consistent across studies (1.2 g

to 2 g via 15 to 30-minute infusion), so it is not clear whether the

same effect would be observed with alternative administrations

(e.g. higher dose, bolus).

The definition of hospital admission may have varied between the

healthcare settings in which these studies were carried out, and

this was not clearly defined in the studies. We accept that variation

exists in the broader health and economic environments and in

health infrastructures, such as the use of clinical decision making

or observation wards, and that this is likely to have influenced

the decision to admit. This variation is likely to have introduced

heterogeneity in the primary outcome.

The previous version of this review (Rowe 2009) suggested the

possibility of greater efficacy of treatment in more severe exacerba-

tions; this partially informed our decision to perform a subgroup

analysis based on severity. We did not find a statistically signifi-

cant difference between the three severity subgroups; however, the

method that we used to allocate baseline severity had limitations.

We based this classification on BTS/SIGN 2012 criteria, but re-

porting of baseline metrics on which this guidance is based was

insufficient in several studies. In studies that subdivided the pop-

ulation on the basis of severity (Bilaceroglu 2001; Bloch 1995;

Bradshaw 2007), subgroups with a more severe condition gained

greater benefit with respect to hospital admission. This suggests

that within-study subgroups may serve as a more reliable way of

assessing severity as an effect modifier by controlling for differ-

ences in other variables that may exist between study protocols.

We were unable to draw conclusions regarding the potential effects

of age on study outcomes, as none of the studies recruited older

adults. It is possible that diagnosis in this age group would be

complicated by important co-morbidities (e.g. chronic obstructive



pulmonary disease (COPD)), and that these might also affect the

safety and effectiveness of IV MgSO4. As such, it is likely that the

conclusions of this review are not applicable to this population, or

to children younger than the age of 12.

Several outcomes showed significant statistical heterogeneity

among studies that was not accounted for by subgrouping results

by severity of exacerbations (heart rate (HR), systolic blood pres-

sure (BP), PEF in L/min, length of hospital stay). For HR, systolic

BP and PEF in L/min, variation may be explained in part by when

and how the measurement was taken, measurement error and the

influence of co-medications. Length of hospital stay is highly de-

pendent on local hospital guidelines and procedures.

We were unable to meta-analyse data related to adverse events

and therefore could not draw conclusions about the safety of IV

MgSO4 in asthma. Some commonly cited adverse events were

consistently reported among the studies; however, the methods of

recording adverse events appeared unsystematic.

Quality of the evidence

We used GRADEpro software to assess the quality of all outcomes;

this assessment is summarised in the text and in the Summary

of findings for the main comparison. Most outcomes were not

downgraded for risk of bias, and in the two cases in which this was

done, the decision was related primarily to insufficient blinding.

It is unclear how this may have affected results for the primary

outcome (i.e. decision to admit), but a sensitivity analysis exclud-

ing studies in which blinding was insufficient or unclear showed

that this bias is unlikely to have significantly affected the pooled

estimate.

Several outcomes were downgraded for inconsistency, that is, sta-

tistical heterogeneity, between studies. In these cases we performed

sensitivity analyses using a random-effects model, which did not

alter conclusions. The clinical source of the statistical heterogene-

ity remains unclear in most cases, as planned subgroup analyses

were performed only on the primary outcome. Most of the sec-

ondary outcomes for which heterogeneity was observed contained

a small number of studies; therefore it is unlikely that subgrouping

of results would have allowed a meaningful distinction between

severity or co-medication subgroups.

Studies included in this review were directly relevant to our review

question with respect to participants recruited, interventions and

comparisons provided, healthcare setting selected, and outcome

measures used, so none of the evidence was downgraded for indi-

rectness.

Four outcomes were downgraded for imprecision on the basis

of their wide confidence intervals (intensive care unit (ICU) ad-

mission, ED treatment duration, PEF in L/min, respiratory rate

(RR)). In each case the review authors made a clinical judgement

regarding the minimal clinically important difference in relation

to the confidence intervals. Moreover, with the exception of ED

treatment duration, evidence from related outcomes (e.g. other

spirometric measures) helped us draw conclusions when impreci-

sion was due to a small number of participants or events.

No outcomes were downgraded for publication bias, although sev-

eral of the secondary outcomes included a small number of stud-

ies. No incidences were identified in which studies stated out-

comes and failed to report them, but this was generally a result

of insufficient reporting of intended outcomes and the fact that

the studies could not be linked to trial registrations. Most studies

were conducted before adherence to trial registration or reporting

standards was common practice, so in most cases we were unable

to definitively judge whether the evidence was compromised as a

result of deliberate or inadvertent selective reporting.

To resolve uncertainties related to risk of bias and missing data, we

made an effort to contact all study authors. We received additional

data from four of these authors (Bilaceroglu 2001; Bloch 1995;

Goodacre 2013; Singh 2008), were unable to obtain current con-

tact details for two (Matusiewicz 1994; Porter 2001) and received

no response from the remaining eight.

Potential biases in the review process

We made every effort to adhere to Cochrane methods during the

review process. All study characteristics and numerical data were

extracted by at least two review authors, and discrepancies were

resolved through discussion. The same was true for risk of bias

ratings, and none of the review authors have conflicting interests.

We performed relatively broad searches that were screened by at

least two review authors independently, and we included studies

regardless of language of publication. As a result, It is unlikely

that any published studies were missed during study selection. In

addition, review authors attempted to contact all study authors to

clarify study methodology or to obtain additional data when details

were not included in the published reports. We received detailed

replies and additional data from four study authors, but in most

cases, it was unclear whether study authors had failed to receive the

request or were simply unable to provide the information required.

The subgroup analysis based on exacerbation severity introduced

the potential for internal bias, despite efforts to remove bias by

consultation with an independent fourth party. Although we were

transparent in the method of classification, an element of subjec-

tivity due to reporting standards was noted in some trials; this

reduced our confidence in the subgroup findings.

Agreements and disagreements with otherstudies or reviews

Our literature search identified five systematic reviews with meta-

analyses comparing use of IV MgSO4 versus placebo in adults

with acute asthma (Alter 2000; Mohammed 2007; Rodrigo 2000;

Rowe 2009; Shan 2013). One of these, Rowe 2009, was a pre-

vious Cochrane review, and Shan 2013, the most recent research



synthesis, included the greatest number of trials (n = 16), 10 of

which are included in this review.

The main outcomes analysed were hospital admissions and spiro-

metric data. None of the existing reviews found a statistically sig-

nificant reduction in hospital admissions across all severity sub-

groups. However Rowe 2009 found a significant reduction in hos-

pital admissions within the more severe group (OR 0.10, 95% CI

0.04 to 0.27) and suggested that IV MgSO4 might play a role in

these more severe exacerbations. Hospital admission data for Shan

2013 were on the border of statistical significance (P value 0.06).

Alter 2000 and Shan 2013 reported significant improvement in

pooled spirometric measures for those receiving IV MgSO4 , whilst

Mohammed 2007 reported weak evidence to support this (SMD

0.25, 95% CI -0.01 to 0.51; P value 0.05). Pooled analyses in

Rodrigo 2000 and Rowe 2009 showed no significant improvement

in lung function for those given IV MgSO4.

In keeping with these reviews, we found evidence that IV MgSO4

improves lung function on a variety of spirometric measures. How-

ever, our findings differ in that when all data regardless of severity

criteria were pooled, a statistically significant reduction in hospital

admissions was seen among those treated with IV MgSO4. We did

not draw firm conclusions regarding the extent to which severity

of exacerbation affects the efficacy of IV MgSO4 because differ-

ences in the ways the studies were conducted made it difficult to

assess the effect of exacerbation severity independent of other ef-

fect moderators.

Several reasons may account for the discrepancies between our

conclusions and those of previous evidence syntheses. Unlike some

previous systematic reviews (Alter 2000; Mohammed 2007; Rowe

2009; Shan 2013), our inclusion criteria did not include pae-

diatric trials. Several additional trials have been published since

the previous version of this review, and this warranted synthesis-

ing of data for adults separately from data for children (Bijani

2001; Bilaceroglu 2001; Boonyavorakul 2000; Bradshaw 2007;

Del Castillo Rueda 1991; Goodacre 2013; Matusiewicz 1994;

Porter 2001; Singh 2008). One of these trials, Goodacre 2013,

is a recent randomised controlled trial with a large sample size;

it accounted for a significant proportion of the total weight in

several of our analyses. Evidence for the use of IV MgSO4 in the

paediatric population will be analysed in a separate Cochrane re-

view, which is currently in production. Some previous syntheses

have included trials of nebulised magnesium sulfate (Mohammed

2007; Rodrigo 2000; Shan 2013), which we did not include, as

this is the subject of an existing Cochrane review (Powell 2012).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

This review provides evidence that a single infusion of 1.2 g or 2 g

IV MgSO4 over 15 to 30 minutes reduces hospital admissions and

improves lung function in adults with acute asthma who have not

responded sufficiently to oxygen, nebulised short-acting beta2-ag-

onists and IV corticosteroids. Differences in the ways the trials

were conducted made it difficult to assess whether the severity of

the exacerbation, or additional co-medications, altered the treat-

ment effect of IV MgSO4. Evidence for other measures of benefit

and safety was limited.

Implications for research

Studies conducted in these populations should clearly define base-

line severity parameters and systematically record adverse events.

Studies recruiting participants with exacerbations of varying sever-

ity should consider subgrouping results on the basis of accepted

severity classifications.

A C K N O W L E D G E M E N T S

We acknowledge Chris Cates for assistance in classifying the base-

line severity of study populations and contributions to clinical in-

terpretation of study findings.

Brian Rowe was the Editor for this review and commented criti-

cally on the review.

We are grateful to study authors who provided additional data

and clarifications (Bilaceroglu 2001; Bloch 1995; Goodacre 2013;

Singh 2008).

CRG Funding Acknowledgement: The National Institute for

Health Research (NIHR) is the largest single funder of the

Cochrane Airways Group.

Disclaimer: The views and opinions expressed herein are those

of the review authors and do not necessarily reflect those of the

NIHR, the NHS or the Department of Health.



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Silverman 2002 {published and unpublished data}

Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang

W, Feldman J, et al.IV magnesium sulfate in the treatment

of acute severe asthma: a multicenter randomized controlled

trial. Chest 2002;122(2):489–97. [: 0012–3692]

Singh 2008 {published and unpublished data}

Singh AK, Gaur S, Kumar R. A randomized controlled

trial of intravenous magnesium sulphate as an adjunct to

standard therapy in acute severe asthma. Iranian Journal of

Allergy, Asthma, and Immunology 2008;7(4):221–9.

Singh AK, Gaur SN, Kumar R. Comparison of efficacy of

intravenous and inhaled magnesium sulphate as an adjunct

to standard therapy in acute severe asthma [Abstract].

European Respiratory Society 18th Annual Congress; Oct

3-7; Berlin. 2008:[P3620].

Skobeloff 1989 {published and unpublished data}

Skobeloff EM, Spivey WH, McNamara RM, Greenspoon

L. Intravenous magnesium sulfate for the treatment of acute

asthma in the emergency department. JAMA 1989;262(9):

1210–3.

Tiffany 1993 {published and unpublished data}∗ Tiffany BR, Berk WA, Todd IK, White SR. Magnesium

bolus or infusion fails to improve expiratory flow in acute

asthma exacerbations. Chest 1993;104(3):831–4.

References to studies excluded from this review

Abreu-Gonzalez 2002 {published data only}

Abreu-Gonzalez J, Rodríguez-Díaz CY. Magnesium and

bronchodilator effect of beta-adrenergic. American Journal

of Respiratory and Critical Care Medicine 2002;165(Suppl

8):A185.

Brunner 1985 {published data only}

Brunner EH, Delabroise AM, Haddad ZH. Effect of

parenteral magnesium on pulmonary function, plasma

cAMP, and histamine in bronchial asthma. Journal of

Asthma 1985;22(1):3–11.



Cairns 1996a {published data only}

Cairns CB, Kraft M. Magnesium attenuates the neutrophil

respiratory burst in adult asthmatic patients. Academic


Harmanci 1996 {published data only}

Harmanci E, Ekici M, Erginel S, Ozdemir N, Ozkan

G. Comparison of effects of nebulized to intravenous

magnesium sulfate on bronchial hyperreactivity and

expiratory flow rate in asthmatic patients. European

Respiratory Journal 1996;9 Suppl 23:34s.

Hill 1996 {published data only}

Hill JM, Britton J. Effect of intravenous magnesium

sulphate on airway calibre and airway reactivity to

histamine in asthmatic subjects. British Journal of Clinical

Pharmacology 1996;42(5):629–31.

Liang 1998 {published data only}

Liang XG. Analysis of the effect of magnesium sulfate in the

treatment of asthmatoid disease. Chinese Journal of Modern

Medicine 1998;8(2):29.

Okayama 1987 {published data only}

Okayama H, Aikawa T, Okayama M, Sasaki H, Mue

S, Takishima T. Bronchodilating effect of intravenous

magnesium sulfate in bronchial asthma. Journal of American

Medical Association 1987;257(8):1076–8.

Rolla 1988 {published data only}

Rolla G, Bucca C, Caria E, Arossa W, Bugiani M, Cesano

L, et al.Acute effect of intravenous magnesium sulfate on

airway obstruction of asthmatic patients. Annals of Allergy

1988;61(5):388–91.

Rolla 1994 {published data only}

Rolla G, Bucca C, Brussino L, Colagrande P. Effect of

intravenous magnesium infusion on salbutamol-induced

bronchodilatation in patients with asthma. Magnesium

Research 1994;7(2):129–33.

Schenk 2001 {published data only}

Schenk P, Vonbank K, Schnack B, Haber P, Lehr S,

Smetana R. Intravenous magnesium sulfate for bronchial

hyperreactivity: a randomized, controlled, double-blind

study. Clinical Pharmacology and Therapeutics 2001;69(5):

365–71.

References to studies awaiting assessment

Abd El Kader 1997 {published data only}

Abd El Kader F. Ventilatory, cardiovascular and metabolic

responses to salbutamol, ipratropium bromide and

magnesium sulfate in bronchial asthma: comparative study.

Alexandria Medical Journal [The] 1997;39(1):43–64.

Additional references

Alter 2000

Alter HJ, Koepsell TD, Hilty WM. Intravenous magnesium

as an adjuvant in acute bronchospasm: a meta-analysis.

Annals of Emergency Medicine 2000;36(3):191–7.

Asthma UK

Asthma UK. Asthma Facts and FAQs. http://

www.asthma.org.uk/asthma-facts-and-statistics (accessed 8

October 2013).

BTS/SIGN 2012

British Thoracic Society/Scottish Intercollegiate Guidelines

Network (BTS/SIGN). British Guideline on the

Management of Asthma. http://www.brit-thoracic.org.uk/

guidelines/asthma-guidelines.aspx (accessed 8 October

2013).

Cairns 1996

Cairns CB, Krafi M. Magnesium attenuates the neutrophil

respiratory burst in adult asthmatic patients. Academic


CDC

Centers for Disease Control and Prevention. Asthma

Surveillance Data. http://www.cdc.gov/asthma/ (accessed

25 November 2013).

DOH 2012

Department of Health. An Outcomes Strategy for

COPD and Asthma: NHS Companion Document.

www.dh.gov.uk/publications (accessed 3 December 2013).

Dominguez 1998

Dominguez LJ, Barbagallo M, Di Lorenzo G, Drago A,

Scola S, Morici G, et al.Bronchial reactivity and intracellular

magnesium: a possible mechanism for the bronchodilating

effects of magnesium in asthma. Clinical Science 1998;95:

137–42.

GINA 2011

Global Initiative for Asthma (GINA). Global Strategy

for Asthma Management and Prevention. http://

www.ginasthma.org/ (accessed 20 October 2013).

Gourgoulianis 2001

Gourgoulianis KI, Chatziparasidis G, Chatziefthimiou A,

Molyvdas PA. Magnesium as a relaxing factor of airway

smooth muscles. Journal of Aerosol Medicine 2001;14(3):

301–7. [PUBMED: 11693841]

Griffiths 2013

Griffiths B, Ducharme FM. Combined inhaled

anticholinergics and short-acting beta2-agonists for initial

treatment of acute asthma in children. Cochrane Database

of Systematic Reviews 2013, Issue 9. [DOI: 10.1002/

14651858.CD000060.pub2]

Griffiths 2014

Griffiths B, Kew Kayleigh M, Michell Clare I, Kirtchuk

L. Intravenous magnesium sulfate for treating children

with acute asthma in the emergency department. Cochrane

Database of Systematic Reviews 2014, Issue 4. [DOI:

10.1002/14651858.CD011050; : CD011050]

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook

for Systematic Reviews of Interventions Version 5.1

[updated March 2011]. The Cochrane Collaboration.

www.cochrane-handbook.org 2011.



Mohammed 2007

Mohammed S, Goodacre S. Intravenous and nebulised

magnesium sulphate for acute asthma: systematic review

and meta-analysis. Emergency Medicine Journal 2007;24:

823–30.

NACA 2006

National Asthma Council Australia. Asthma Management

Handbook. http://www.nationalasthma.org.au/handbook

(accessed 25 November 2013).

NAEPP 2007

National Asthma Education and Prevention Program.

Guidelines for the Diagnosis and Management of Asthma.

www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

(accessed 25 November 2013).

Powell 2012

Powell C, Dwan K, Milan SJ, Beasley R, Hughes R,

Knopp-Sihota JA, et al.Inhaled magnesium sulfate in

the treatment of acute asthma. Cochrane Database of

Systematic Reviews 2012, Issue 12. [DOI: 10.1002/

14651858.CD003898.pub5]

Review Manager (RevMan)

The Nordic Cochrane Centre, The Cochrane Collaboration.

Review Manager (RevMan). 5.2. Copenhagen: The Nordic

Cochrane Centre, The Cochrane Collaboration, 2012.

Rodrigo 2000

Rodrigo G, Rodrigo C, Burschtin O. Efficacy of magnesium

sulfate in acute adult asthma: a meta- analysis of randomized

trials. American Journal of Emergency Medicine 2000;18(2):

216–21.

Rowe 2013

Rowe BH. Intravenous and inhaled MgSO4 for acute

asthma. The Lancet Respiratory Medicine 2013;1(4):276–7.

[DOI: 10.1016/S2213-2600(13)70097-3]

Santanello 1999

Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL.

What are minimal important changes for asthma measures

in a clinical trial?. European Respiratory Journal 1999;14(1):

23–7.

Shan 2013

Shan Z, Rong Y, Yang W, Wang D, Yao P, Xie J, Liu L.

Intravenous and nebulized magnesium sulfate for treating

acute asthma in adults and children: a systematic review and

meta-analysis. Respiratory Medicine 2013;107(3):321–30.

Spivey 1990

Spivey WH, Skobeloff EM, Levin RM. Effect of magnesium

chloride on rabbit bronchial smooth muscle. Annals of


Teoh 2012

Teoh L, Cates C, Hurwitz M, Acworth JP, Van Asperen P,

Chang AB. Anticholinergic therapy for acute asthma in

children. Cochrane Database of Systematic Reviews 2012,

Issue 4. [DOI: 10.1002/14651858.CD003797.pub2]

References to other published versions of this review

Kew 2014

Kew KM, Kirtchuk L, Michell CI, Griffiths B. Intravenous

magnesium sulfate for treating adults with acute asthma

in the emergency department. Cochrane Database of

Systematic Reviews 2014, Issue 1. [DOI: 10.1002/

14651858.CD010909]

Rowe 2009

Rowe BH, Bretzlaff J, Bourdon C, Bota G, Blitz S, Camargo

CA. Magnesium sulfate for treating exacerbations of acute

asthma in the emergency department. Cochrane Database

of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/

14651858.CD001490]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Bijani 2001

Methods Design: randomised, double-blind, placebo-controlled study based in Iran. No infor-

mation provided regarding location of trial or dates when it was carried out

Final measurement of outcomes performed at 180 minutes with participants followed

for 6 hours

Participants Population: 81 participants randomly assigned to control (33) or IV MgSO4 infusion

(48)

Inclusion criteria: asthmatic individuals aged 12 to 85 years with an exacerbation of

asthma and a peak expiratory flow (PEF) < 200 L/min who had taken bronchodilators and

corticosteroids and required assisted ventilation. All participants who did not respond

to treatment during the next 6 hours selected for investigation

Exclusion criteria: not reported

Interventions Control group: 100 mL normal saline infused over 30 to 45 minutes after 6 hours of

no response to standard treatment

IV MgSO4 group: 25 mg/kg in 100 mL normal saline infused over 30 to 45 minutes

after 6 hours of no response to standard treatment

Co-interventions: All participants received oxygen, nebulised oxygen, nebulised salbu-

tamol, IV aminophylline and corticosteroids

Outcomes PEF; breathing rate; cyanosis; diaphoresis; use of respiratory muscles; ABGs all measured

at baseline

Notes Baseline severity of population: life threatening (based on 31% predicted PEF, respi-

ration rate 35 breaths per minute)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk ’Randomised’ but no information provided

as to how this was done

Allocation concealment (selection bias) Unclear risk No information provided

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk ’Double-blind’ study; IV MgSO4 and nor-

mal saline in ’identical containers’

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk ’Double-blind’ study; investigators report

that ’decoding was done at the completion

of the study.’ However the study authors do

not specifically report who was measuring

outcomes



Bijani 2001 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk No withdrawal rates provided

Selective reporting (reporting bias) Low risk Everything reported except ABG (but this

is not a primary outcome). No protocol

available. Otherwise all outcomes well re-

ported

Bilaceroglu 2001

Methods Design: Randomised, single-blind trial based in Turkey. Trial was carried out in a spe-

cialist respiratory hospital in Turkey between December 1995 and December 1996

Final measurement of outcomes performed at 210 minutes, and participants followed

up for 1 week afterward

Participants Population: 81 participants randomly assigned to Group 1-moderate asthma (PEF >

40%) (n = 50) or Group 2-severe asthma (PEF < 40%) (n = 31) Within Group 1,

participants randomly assigned to placebo (salbutamol + placebo) (n = 27) or intervention

(salbutamol + magnesium) (n = 23). Within Group 2, participants randomly assigned

to placebo (salbutamol + corticosteroid + placebo) (n = 14) or intervention (salbutamol

+ corticosteroid + magnesium) (n = 17)

Inclusion criteria: Asthmatic participants (defined by American Thoracic Society Cri-

teria) aged 6 to 65 years (average age 35 years) with PEF increasing by < 50% and/or

FEV1 < 75% after a single salbutamol nebuliser (2.5 mg salbutamol in 2.5 mL saline)

Exclusion criteria: diabetes mellitus, congestive heart failure, hypertension, chronic

renal failure,

fever > 38 ºC, pneumonia, under mechanical ventilation and/or having suspicion of

pregnancy. Furthermore, participants with > 50% increase in PEF after beta-agonist

inhalation, or with FEV1 higher than 75% of predicted value at presentation or after

inhaled beta-agonist (response to treatment)

Interventions Control group: Group 1 given salbutamol + placebo (100 cc of 5% dextrose solution).

Group 2 given salbutamol (2.5 mg nebulised) + corticosteroid (125 mg prednisolone) +

placebo (100 cc of 5% dextrose solution). In both groups, these were given at the 30th

minute of the participant’s arrival

IV MgSO4 group: Group 1 given salbutamol + 2 mg IV MgSO4 in 100 cc dextrose

solution. Group 2 given salbutamol (2.5 mg nebulised) + corticosteroid (125 mg pred-

nisolone) + 2 mg MgSO4 in 100 cc dextrose solution. Both groups given treatment at

the 30th minute of their arrival

Co-interventions: All participants received oxygen if PaO2 < 60mmHg

Outcomes PEF, FEV1 and hospitalisation, length of hospital stay; change in systolic arterial pressure;

change in respiration rate; dyspnoea; blood gases; serum Mg; calcium; specific adverse

events

Notes Baseline severity of population: Moderate and severe groups in the trial reclassified as

severe and life threatening, respectively, for consistency with other study classifications

and BTS guidelines (BTS/SIGN 2012)



Bilaceroglu 2001 (Continued)

Risk of bias



bias)

Unclear risk ’Randomised’ study using 1:1 tables but no

other information provided regarding se-

quence generation



(performance bias)

All outcomes

High risk ’Single-blind’ study. Only participants

blinded to the intervention


bias)

All outcomes

High risk ’Single-blind’ study. Only participants

blinded to the intervention


All outcomes

Low risk Clear withdrawal rates provided. No with-

drawals described after suitable participants

(n = 81) were identified for randomisation.

(Data from all excluded participants (n =

218) before randomisation not used in the

analysis)

Selective reporting (reporting bias) Unclear risk Results given for stated outcomes, but some

data given only in graph format. Raw data

not provided

Bloch 1995

Methods Design: randomised, double-blind, placebo-controlled study based in the USA. Trial

carried out in 2 EDs of a voluntary and a university hospital in the USA between August

1990 and December 1991

Final measurement of outcomes performed at 240 minutes and participants followed up

for 7 days

Participants Population: 149 participants randomly assigned to control (68) or IV MgSO4 (67)

Inclusion criteria: asthmatic participants aged 18 to 65 years, with an exacerbation

defined as FEV1 < 75% predicted before and after a single dose of salbutamol

Exclusion criteria: past medical history of congestive cardiac failure, diabetes mellitus,

angina or chronic kidney disease; temperature > 38 ºC; pregnancy; pneumonia; requiring

intubation; unable to perform spirometry; unable to consent; FEV1 > 75% before or

after single dose of salbutamol

Interventions Control group: 50 mL of 0.9% normal saline given 30 minutes after entry and infused

over 20 minutes

IV MgSO4 group: 2 g IV MgSO4 in 50 mL 0.9% normal saline given 30 minutes after



Bloch 1995 (Continued)

entry and infused over 20 minutes

Co-interventions: All participants received Inhaled albuterol (2.5 mg in 2.5 mL normal

saline) on arrival. If FEV1 < 40% predicted, or if participants had received oral corticos-

teroids within the past 6 months, they received 125 mg IV methylprednisolone within

30 minutes of presentation. Some participants were already taking theophylline before

the time of presentation

Outcomes Hospitalisation rate; FEV1 at 2 hours after baseline; repeat hospitalisations; respiratory

rate; heart rate; systolic blood pressure; Borg score; wheeze score; adverse events

Notes Funded by the Nina Weisman Pulmonary Research Fund

Baseline severity of population: moderate and severe groups in the trial reclassified as

severe and life threatening, respectively, for consistency with other study classifications

and BTS guidelines (BTS/SIGN 2012)

Risk of bias



bias)

Low risk Randomly assigned by the pharmacy using

’computer-generated tables’

Allocation concealment (selection bias) Low risk ’All physicians were blinded to the ran-

domisation that was done by the pharmacy’


(performance bias)

All outcomes

Low risk ’Double -blind’ but no description of how

interventions were disguised


bias)

All outcomes

Low risk No subjective assessor-rated outcomes, and

the investigators remained blind


All outcomes

Low risk Attrition rates reported: ’Fourteen patients

were excluded after randomisation.’ ’Four

patients were included as an intention to

treat because the protocol was violated…’

’In six patients their baseline FEV1 was un-

available and these were included in the

analysis as a whole and excluded from sub-

group analysis’

Overall small attrition numbers

Selective reporting (reporting bias) Low risk Published report provided data only at one

of the prespecified time points; FEV1 was

provided graphically, but the study author

provided additional data upon request



Boonyavorakul 2000

Methods Design: randomised, double-blind, placebo-controlled study based in Thailand. Trial

carried out in a single ED between March and November 1997

Final measurement of outcomes performed at 240 minutes with no further follow-up of

participants


Inclusion criteria: asthmatic individuals aged 15 to 65 years with acute severe asthma,

defined as having a severity score > 4, who consented to enter the trial

Exclusion criteria: co-morbidities including ischaemic heart disease, hypertension, di-

abetes mellitus, chronic kidney disease, infection or pregnancy; or a FISCHL Index < 4

Interventions Control group: 2 mL of sterile water in 50 mL 0.9% normal saline

IV MgSO4 group: 2 g of Mg SO4 in 50 mL 0.9% normal saline

Co-interventions: All participants received 5 mg intravenous dexamethasone, 2.5 mg

nebulised salbutamol at 0, 20, 40, 60 minutes and oxygen via mask if necessary

Outcomes Hospitalisation rate; severity score FISCHL Index at 0, 60, 120, 180, 240 minutes

(comprising pulse rate, respiratory rate, PEF, dyspnoea, accessory muscle use and wheeze)

Notes Baseline severity of population: life threatening (based on comparison of vital stats [HR

125 bpm, respiration rate 33] with other studies with multiple baseline measurements)

Risk of bias



bias)

Low risk Randomly assigned using a ’computer gen-

erated random list’

Allocation concealment (selection bias) Unclear risk Not reported


(performance bias)

All outcomes

Low risk Double-blind study. ’Study investigators

and patients were blind to whether they ad-

ministered/received MgSO4 or placebo’


bias)

All outcomes

Low risk ’Only 2 physicians took responsibility for

caring for patients in ED. They measured

all clinical data and made the decision re-

garding admission. They were blinded and

the protocol was not violated during the

study’


All outcomes

Low risk ’One patient in the placebo group didn’t

consent and so was removed from the

group.’ Equal numbers of withdrawals

from both groups (17 magnesium and 16

placebo)



Boonyavorakul 2000 (Continued)

Selective reporting (reporting bias) High risk Incomplete reporting: only the admission

data given. Severity scores given only in

terms of ’variance’ and no raw data pro-

vided

Bradshaw 2007

Methods Design: randomised, double-blind, placebo-controlled study based in Edinburgh. Trial

carried out in a teaching hospital. No information provided regarding the dates of the

study

Final measurement of outcomes performed at 60 minutes and no follow-up of partici-

pants reported


Inclusion criteria: asthmatic individuals aged 16 years and older, with asthma exacer-

bation defined as PEF < 75%

Exclusion criteria: co-morbidities including chronic obstructive pulmonary disease,

pneumonia, congestive cardiac failure, coronary artery disease, chronic kidney disease,

hypertension or pregnancy; participants who are unable to carry out peak flow measure-

ments

Interventions Control group: 50 mL 0.9% normal saline infused over 15 minutes

IV MgSO4 group: 1.2 g IV MgSO4 in 50 mL 0.9% normal saline infused over 15

minutes

Co-interventions: All participants received 35% oxygen, 5 mg nebulised salbutamol,

500 mcg nebulised ipratropium bromide, 200 mg IV hydrocortisone

Outcomes % predicted PEF at 60 minutes (repeated at 15, 30, 45 and 60 minutes), hospital

admission rates (decision made at 60 minutes), blood pressure and pulse at 60 minutes

Notes Baseline severity of population: Moderate, severe and life-threatening classifications

within the trial were not changed

Risk of bias



bias)

Low risk ’Randomised using random number gen-

eration under the control of hospital phar-

macy’

Allocation concealment (selection bias) Low risk Randomisation done by pharmacy and

physicians remained blinded


(performance bias)

All outcomes

Low risk ’Double blind, placebo controlled study’.

IV MgSO4 and placebo ’identical in ap-

pearance’



Bradshaw 2007 (Continued)


bias)

All outcomes

Low risk No subjective assessor-rated outcomes (3 ×

PEF), and the investigators remained blind.

The ’decision to admit/discharge was made

by the attending physician’


All outcomes

Low risk Well reported. 21 participants excluded

prior to randomisation. None after that

Selective reporting (reporting bias) High risk Incomplete reporting- primary and sec-

ondary outcomes given at 60 minutes but

not at other intervals (data given in graph

format but no raw data available, making

analysis difficult)

Del Castillo Rueda 1991

Methods Design: randomised, no information on blinding, placebo-controlled study based in

Spain. Trial carried out in one hospital in Madrid

Information regarding duration of the trial and follow-up of participants not provided

Participants Population: 16 participants randomly assigned to control (6) and IV MgSO4 (10)

Inclusion criteria: participants with acute asthma. No details provided regarding age or

how acute asthma was defined


Interventions Control group: not reported

IV MgSO4 Group: 1.2 g of IV MgSO4 in physiological fluid infused over 20 minutes

Co-interventions: All participants received corticosteroids and beta-2 agonists

Outcomes PEF; ABG; hospitalisation rate; length of stay; adverse events

Notes Abstract only

Baseline severity of population: unknown, but did not contribute data to the primary

analysis

Risk of bias



bias)

Unclear risk Authors describe the study as ’randomised,

double blind,’ but no details given about

the blinding process. Difficult to comment

based on the abstract alone

Allocation concealment (selection bias) Unclear risk No information provided. Difficult to

comment based on the abstract alone



Del Castillo Rueda 1991 (Continued)


(performance bias)

All outcomes

Unclear risk No information provided. Difficult to



bias)

All outcomes




All outcomes



Selective reporting (reporting bias) Unclear risk No information provided. Difficult to


Goodacre 2013

Methods Design: randomised, double-blind, placebo-controlled study based in the UK. Trial

carried out in the EDs of 34 hospitals across the UK between 30 July 2008 and 30 June

2012

Final measurement of outcomes performed at 120 minutes; however decision to admit

made at 240 minutes and participants followed up for 1 month


and one other group that was not relevant to our study (nebulised magnesium; n = 339)

Inclusion criteria: asthmatic individuals aged 16 years and older with severe acute

asthma (defined as PEF < 50%, respiratory rate > 25 breaths/min, heart rate > 110 bpm,

unable to complete sentences)

Exclusion criteria: life-threatening exacerbations, contraindications to study drugs (e.

g. pregnancy, chronic kidney disease, liver failure, heart block, high serum magnesium

levels), participants who are unable to consent, previous participants in the 3Mg trial,

those who had received magnesium in the previous 24 hours


IV MgSO4 group: 2 g MgSO4 in 100 mL 0.9% normal saline infused over 20 minutes

Co-interventions: All participants received oxygen, 5 mg nebulised salbutamol, 500 mcg

nebulised ipratropium bromide and oral prednisolone during recruitment, followed by 5

mg salbutamol added to each trial nebuliser. Other treatments allowed at the discretion

of the clinician

Outcomes Hospital admissions (after ED treatment or within the next 7 days); participant breath-

lessness (VAS score), mortality; adverse events; use of ventilation or respiratory support

Notes Funded by the UK National Institute for Health Research Health Technology Assessment

Programme

Baseline severity of population: We classified baseline severity as moderate, based on

PEF of 433 L/min and PEF percentage predicted of 52%

Risk of bias



Goodacre 2013 (Continued)



bias)

Low risk Randomly assigned using telephone or In-

ternet randomisation system managed by

Sheffield Clinical Trials Research Unit

Allocation concealment (selection bias) Low risk ’Participants were allocated to numbered

treatment packs kept in the ED’


(performance bias)

All outcomes

Low risk ’Double blind placebo controlled study.’

Numbered treatment packs used. Not clear

whether these were identical in appearance


bias)

All outcomes

Low risk ’Participants, hospital staff and research

staff were masked to allocated treatment’


All outcomes

Low risk Well documented: ’25 withdrew without

starting trial drug, were recruited in error or

could not be allocated to a treatment pack’

Selective reporting (reporting bias) Low risk Primary outcomes well reported in the pub-

lished paper, but no information provided

regarding clinical data (e.g. BP, RR, HR)

or participant satisfaction/QOL data (po-

tentially reported elsewhere). However the

author did supply all of this information on

request

Green 1992

Methods Design: prospective unblinded trial (no placebo and unclear whether randomised) based

in California, USA. Trial carried out in a single ED of an urban teaching hospital between

29 March 1990 and 21 March 1991

Final measurement of outcomes time point unclear

Participants Population: 137 participants allocated to IV MgSO4 treatment or no IV MgSO4 treat-

ment on alternate days of the week

Inclusion criteria: asthmatic individuals aged 18 to 65 years with an exacerbation of

asthma (no further definition)

Exclusion criteria: co-morbidities including ischaemic heart disease, hypertension,

angina, congestive cardiac failure, heart block, chest pain, metastatic cancer, chronic kid-

ney disease, temperature > 38.3 ºC, blood pressure < 120 systolic, pregnancy, pneumonia

or requiring intubation

Interventions Control group: no IV MgSO4 given

IV MgSO4 Group: 2 g IV MgSO4 in 50 mL D5W over 20 minutes within 45 minutes

of treatment initiation



Green 1992 (Continued)

Co-interventions: All participants received oxygen, 2.5 mg inhaled albuterol, 125 mg

IV methylprednisolone. Other medications (e.g. theophylline, injectable beta-agonists,

epinephrine) were allowed at the discretion of the attending physician

Outcomes Hospitalisation rate; ED treatment time (for those discharged); adverse events; relapse

rate; PEF change from baseline; length of hospital stay

Notes Baseline severity of population: severe (based on low PEF L/min 143 and high vital

stats, HR 108 and respiration rate 29)

Risk of bias



bias)

High risk ’Patients presenting on odd days were given

magnesium and those on even days did not

receive magnesium’

Allocation concealment (selection bias) High risk Allocation dependent on the days they pre-

sented. Unblinded and not randomised


(performance bias)

All outcomes

High risk ’Physicians were not blinded to patient ran-

domisation; however, patients and respira-

tory therapists were unaware that a study

was being performed’


bias)

All outcomes

High risk Respiratory therapists (who were measur-

ing the PEF) ’were unaware that a study

was going on,’ but no formal blinding at all


All outcomes

Unclear risk Reported as follows: 217 participants in to-

tal. 80 were repeats and so were excluded

(although it is unclear from which groups

these came), and 17 others were removed

from data analysis because of misplaced

records (total 97/217). No evidence of ITT.

Final group sizes of quite equal size: 58 and

62

Selective reporting (reporting bias) Unclear risk All outcome data given but not clearly de-

scribed as primary or secondary outcomes

in the initial methodology



Matusiewicz 1994

Methods Design: unclear. Based in Scotland but unclear as to location where the trial was carried

out and during what dates

Final measurement of outcomes performed at 60 minutes and information about follow-

up of participants not provided

Participants Population: 131 participants allocated to control (67) or IV MgSO4 (64)

Inclusion criteria: Adults (age not specified) with acute severe asthma (defined as PEF

< 250 or 50% of best previous PEF)



IV MgSO4 group: 1.2 mg IV MgSO4 in 50 mL 0.9% normal saline infused over 15

minutes

Co-interventions: All participants received 5 mg nebulised salbutamol, 500 mcg neb-

ulised ipratropium bromide, oxygen, 200 mg IV hydrocortisone. Aminophylline was

given at the discretion of the attending physician

Outcomes PEF at 15, 30, 45, 60 minutes; hospitalisation rate

Notes Baseline severity of population: We have classified this population as severe based on

inclusion criteria of PEF < 250 L/min and < 50% predicted

Risk of bias



bias)



Allocation concealment (selection bias) Unclear risk No information provided. Difficult to



(performance bias)

All outcomes

Unclear risk ’Double blind placebo controlled parallel

group study.’ No mention of randomisa-

tion nor details of blinding. Difficult to



bias)

All outcomes




All outcomes



Selective reporting (reporting bias) Unclear risk No information provided. Difficult to




Porter 2001

Methods Design: randomised, double-blind, placebo-controlled trial based in Philadelphia, USA.

Trial carried out in a single urban ED, the dates of which are not specified

Final measurement of outcomes performed at 60 minutes with no follow-up of partici-

pants


Inclusion criteria: asthmatic individuals aged 18 to 55 years with an exacerbation (de-

fined as PEF < 100 or < 25% predicted) and able to consent

Exclusion criteria: co-morbidities including pneumonia, chronic kidney disease, con-

gestive cardiac failure, previous myocardial infarction, hypertension, pregnancy or pos-

sibly requiring intubation

Interventions Control group: 50 mL 0.9% normal saline given immediately

IV MgSO4 group: 2 g MgSO4 in 50 mL 0.9% normal saline given immediately

Co-interventions: All participants received 2.5 mg nebulised albuterol sulfate, 125 mg

IV methylprednisolone, oxygen and repeated albuterol every 20, 40 and 60 minutes

Outcomes PEF (at 60 minutes), hospitalisation rate; Borg score; adverse effects of hypotension and

hyporeflexia

Notes Baseline severity of population: life threatening (based on PEF 88.5 L/min and high

vital stats HR 110 and respiration rate 31)

Risk of bias



bias)

Low risk ’Randomised using a random number gen-

erator which assigned the code’

Allocation concealment (selection bias) Low risk ’Enrolment packs containing data record-

ing sheets and study solutions in random

order were prepared by the Pharmacy.’

Saline and magnesium identical in appear-

ance


(performance bias)

All outcomes

Low risk ’Double blind’ study. ’Investigators, other

caretakers and patients were unaware of

contents of the study solution’


bias)

All outcomes

Low risk ’Investigators, other caretakers and patients

were unaware of contents of the study so-

lution’


All outcomes

Unclear risk No attrition data specifically reported.

Comment that the same participant pre-

senting more than once was not used, in-

dicating that investigators always used the

first presentation for analysis



Porter 2001 (Continued)

Selective reporting (reporting bias) Unclear risk Primary outcomes reported as stated at T

= 60. However incomplete reporting for

other time points

Silverman 2002

Methods Design: randomised, double-blind, placebo-controlled study based in the United States

of America (USA). Trial carried out in the EDs of eight hospitals in the USA, but dates

during which this occurred not reported

Final measurement of outcomes performed at 240 minutes and participants followed up

for seven days


Inclusion criteria: asthmatic individuals aged 18 to 60 years with an exacerbation (de-

fined as FEV1 < 30%) who were able to stay for 4 hours and consented to being involved

in the trial

Exclusion criteria: co-morbidities such as chronic obstructive pulmonary disease or

other chronic lung disease, pneumonia, temperature > 38.9 ºC, congestive cardiac fail-

ure, coronary artery disease, diabetes mellitus, chronic kidney disease, hypertension,

pregnancy, requiring intubation or unable to do spirometry

Interventions Control group: 50 mL ’like appearing solution’ infused over 10 to 15 minutes and given

at 30 minutes

IV MgSO4 group: 2 g IV MgSO4 in 50 mL 0.9% normal saline infused over 10 to 15

minutes and given at 30 minutes

Co-interventions: All participants received 2.5 mg nebulised 0.5% albuterol with 100%

oxygen, 125 mg IV methylprednisolone. Albuterol subsequently given at 30, 60, 120

and 180 minutes

Outcomes FEV1 (at 240 minutes), hospitalisation rate; relapse rate; vital signs; Borg scale; PEF (all

at 30 and 240 minutes)

Notes Funded in part by the Max and Victoria Dreyfus Foundation

Baseline severity of population: life threatening (based on PEF 27% predicted, FEV1

23% predicted)

Risk of bias



bias)

Low risk Randomly assigned using a 1:1 ratio ran-

domisation table unique for each centre

Allocation concealment (selection bias) Low risk ’Study pharmacists placed drug or placebo

in identically appearing vials, with only the

study ID on the label’



Silverman 2002 (Continued)


(performance bias)

All outcomes

Low risk ’Double blind, placebo-controlled’


bias)

All outcomes

Low risk Investigators blinded (’FEV1 results were

reviewed blindly by the 2 investigators’)


All outcomes

Unclear risk Well-documented attrition rate n = 70

(28%); these ’were retained in the inten-

tion to treat data set.’ However data for in-

dividual arms not given

Selective reporting (reporting bias) Low risk All outcome data given

Singh 2008

Methods Design: randomised, single-blinded, placebo-controlled trial based in Delhi, India. Trial

carried out in a single ED at the Chest Institute

Final measurement of outcomes performed at 180 minutes with no further participant

follow-up

Participants Population: 70 participants of South Asian origin randomly assigned to control (30)

and IV MgSO4 (30)

Inclusion criteria: asthmatic individuals aged 18 to 60 years with a severe exacerbation

(as defined by GINA) and an FEV < 30% predicted on presentation, who were able to

remain in the department for 3 hours

Exclusion criteria: co-morbidities such as chronic obstructive pulmonary disorder

(COPD) or other chronic lung disease, cardiac, renal or hepatic dysfunction, pregnancy

or lactating or requiring intubation or unable to do spirometry

Interventions Control group: 250 mL 0.9% normal saline infused over 20 minutes at 30 minutes

IV MgSO4 group: 2 g IV MgSO4 in 250 mL 0.9% normal saline infused over 20

minutes at 30 minutes

Co-interventions: All participants received 100 mg IV hydrocortisone on arrival (0

minutes). They then received a nebulising solution consisting of: 2.5 mg nebulised

salbutamol, 1.5 mL ipratropium bromide and 2.5 mL normal saline with 100% oxygen

at 0, 20 and 40 minutes

Outcomes Change in FEV1 % predicted, hospitalisation rate; cyanosis; stats; vital signs; Borg score

Notes Trial done as part of an MD dissertation project funded by a grant from University of

Delhi, India

Baseline severity of population: life threatening (based on PEF 22% predicted, FEV1

38% predicted, and high HR 127 bpm)

Risk of bias



Singh 2008 (Continued)



bias)

Low risk Randomly assigned using a 1:1 ration ran-

domisation table

Allocation concealment (selection bias) Low risk Random number tables used. ’Individual

random numbers were kept in separate en-

velopes so the concealment could be main-

tained until the patient was included in the

assigned group.’ Placebo described only as

’like appearing placebo’


(performance bias)

All outcomes

Unclear risk Described as a ’single blind study.’ However

further information from the study author

confirmed that participants and assessors

of spirometric and clinical outcomes were

blinded to the treatment given, and the de-

cision to admit was made by chief residents

blinded to type of treatment given


bias)

All outcomes

Low risk Study authors do not specify in the pub-

lished paper who does the spirometry and

clinical examination of the respiratory sys-

tem at each time interval, but further in-

formation from the study authors confirms

that participants and assessors of spiromet-

ric and clinical outcomes were blinded to

the treatment given

Decision to hospitalise or discharge was

made by ED staff blinded to group alloca-

tion


All outcomes

Low risk This is clearly given for both groups (5 in

each group), so it is equal, and total with-

drawal percentage is low at 14%

Selective reporting (reporting bias) Low risk Good reporting of primary outcomes at all

time points for FEV1 and at 120 minutes

for Borg scale and clinical indicators



Skobeloff 1989

Methods Design: randomised, double-blind, placebo-controlled study based in Philadelphia,

USA. Trial carried out in a single ED between August 1987 and February 1988

Final measurement of outcomes performed at 45 minutes, with the decision to admit at

240 minutes and no reported follow-up of participants


Inclusion criteria: asthmatic individuals aged 18 to 70 years with an exacerbation (initial

PEF < 200 L/min) and defined as poor responders to initial treatment

Exclusion criteria: initial PEF > 200 L/min, rectal temperature > 38 ºC, systolic blood

pressure < 120, history of kidney disease, pregnancy, purulent sputum or infiltrate on

chest


IV MgSO4 group: 1.2 g IV MgSO4 in 50 mL of 0.9% normal saline infused over 20

minutes

Co-interventions: All participants received nebulised metaproterenol sulphate 0.3 mL

in 3.0 mL of saline or albuterol sulphate 0.5 mL in 2.5 mL of saline at the discretion of

the physician, 125 mg IV methylprednisolone sodium succinate and a loading dose of

theophylline based on participant levels. This was followed by a maintenance infusion

of 0.5 mg/kg/h. 45 to 60 minutes after initial treatment, a second nebulised treatment

was given

Outcomes PEF; hospitalisation rate; heart rate; respiration rate; mean arterial pressure

Notes Baseline severity of population: severe, based on estimates from baseline characteristics

graphs (HR ~ 100 bpm, RR ~ 28 rpm, PEF ~ 150 L/min)

Risk of bias



bias)

Unclear risk ’Coded from a randomised list’

Allocation concealment (selection bias) Low risk Placebo/magnesium solutions prepackaged

in identical vials by the pharmacy and

coded from a randomised list


(performance bias)

All outcomes

Low risk Double-blinded, randomised, placebo-

controlled trial. Solutions ’prepackaged in

identical vials’


bias)

All outcomes

Low risk Double-blinded. ’The decision to admit or

discharge was made by the physician caring

for the patient and not influenced by the

investigator’


All outcomes

Low risk Withdrawals few and well commented on

(2/14 excluded)



Skobeloff 1989 (Continued)

Selective reporting (reporting bias) High risk All predetermined outcomes reported (ex-

cept deep tendon reflexes, but the relevance

of this is uncertain). However raw data not

provided. Only graphs for some outcomes

Tiffany 1993

Methods Design: randomised, double-blind, placebo-controlled based in Detroit, USA. Trial

carried out in a single ED, the dates of which are not provided

Final measurement of outcomes performed at 260 minutes with no reported follow-up

of participants

Participants Population: 48 participants randomly assigned to control (21) and IV MgSO4 (15), and

one other group that was not relevant to this review (continuous IV MgSO4 infusion n

= 12)

Inclusion criteria: asthmatic individuals aged 18 to 60 years with an exacerbation who

have consented to being involved in the trial

Exclusion criteria: first episode of wheeze, history of chronic lung disease, temperature

> 38.2 ºC, chronic kidney disease, congestive cardiac failure, requiring intubation and

initial PEF > 200 L/min

Interventions Control group: 2 g stat of 0.9% normal saline over 20 minutes followed by a placebo

infusion over 4 hours

IV MgSO4 group: 2 g IV MgSO4 in 0.9% normal saline over 20 minutes followed by

placebo infusion over 4 hours

Co-interventions: All participants received 2.5 mg nebulised albuterol 30 minutes apart,

125 mg IV methylprednisolone, followed by a third albuterol aerosol treatment and an

aminophylline loading dose and infusion to keep levels at 15 mg/L

Outcomes PEF and FEV1

Notes Baseline severity of population: life threatening (based on PEF L/min 115, and FEV1

0.95 L)

Risk of bias



bias)

Low risk Randomly assigned using a ’computerised

random number generation under the con-

trol of the hospital pharmacy’



(performance bias)

All outcomes

Low risk ’Double blind, placebo controlled study.’

’Investigators and patients were blinded to

patient assignment to the study groups’



Tiffany 1993 (Continued)


bias)

All outcomes

Low risk Best of 3 PEF and FEV1 values measured

(objective measurements). ’Clinical deci-

sion making (i.e. decision to admit) was left

to attending physicians’


All outcomes

Unclear risk No information provided

Selective reporting (reporting bias) High risk Incomplete and no raw data reported. Re-

sults given only as variances and graphs

ABGs: Arterial blood gases; BP: Blood pressure; BTS: British Thoracic Society; COPD: Chronic obstructive pulmonary disease; ED:

Emergency department; FEV1: Forced expiratory volume in 1 second; GINA: Global Initiative for Asthma; HR: Heart rate; ITT:

Intent-to-treat; IV: Intravenous; Mg: Magnesium; MgSO4: Magnesium sulfate; PaO2: Partial pressure of oxygen in arterial blood;

PEF: Peak expiratory flow; RR: Respiratory rate; VAS: Visual analogue scale.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Abreu-Gonzalez 2002 Not an ED study. Design did not match inclusion criteria, laboratory study

Brunner 1985 Not an ED study. Design did not match inclusion criteria, laboratory study (’each subject serving as his own

control’)

Cairns 1996a Not an ED study. Design did not match inclusion criteria, laboratory study

Harmanci 1996 Nebulised versus IV MgSO4. Does not appear to have a placebo arm

Hill 1996 Not an ED study. Design did not match inclusion criteria, laboratory study

Liang 1998 No diagnosis of asthma. Child study

Okayama 1987 Not an ED study. Portion of the sample inpatients

Rolla 1988 Not an ED study. Design did not match inclusion criteria and non-emergency patients

Rolla 1994 Not an ED study

Schenk 2001 No diagnosis of asthma



Characteristics of studies awaiting assessment [ordered by study ID]

Abd El Kader 1997

Methods ’Comparative study’

Participants Patients with bronchial asthma

Interventions Salbutamol, ipratropium bromide and magnesium sulfate

Outcomes Ventilatory, cardiovascular and metabolic responses

Notes Numerous attempts made to locate the paper, but no library holdings found



D A T A A N D A N A L Y S E S

Comparison 1. IV MgSO4 versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Hospital admissions 11 1769 Odds Ratio (M-H, Fixed, 95% CI) 0.75 [0.60, 0.92]

2 Intensive care unit (ICU)

admissions

1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected

3 High dependency unit (HDU)

admissions

1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected

4 ED treatment duration

(minutes)

1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

5 Length of hospital stay (days) 3 949 Mean Difference (IV, Fixed, 95% CI) -0.03 [-0.33, 0.27]

6 Readmission 2 887 Odds Ratio (M-H, Fixed, 95% CI) 2.30 [0.66, 7.99]

7 Heart rate (bpm) 4 1195 Mean Difference (IV, Fixed, 95% CI) -2.37 [-4.13, -0.61]

8 Respiratory rate (breaths/min) 4 1195 Mean Difference (IV, Fixed, 95% CI) -0.28 [-0.77, 0.20]

9 Systolic blood pressure (mmHg) 4 1264 Mean Difference (IV, Fixed, 95% CI) 0.08 [-1.89, 2.05]

10 FEV1 (% predicted) 4 523 Mean Difference (IV, Fixed, 95% CI) 4.41 [1.75, 7.06]

11 PEF (% predicted) 3 1129 Mean Difference (IV, Fixed, 95% CI) 4.78 [2.14, 7.43]

12 PEF (L/min) 8 1460 Mean Difference (IV, Fixed, 95% CI) 17.40 [8.64, 26.17]

13 Borg Dyspnoea Scale score 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only

Comparison 2. IV MgSO4 versus placebo (subgroup and sensitivity analyses)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Hospital admissions (by severity) 11 1743 Odds Ratio (M-H, Fixed, 95% CI) 0.76 [0.62, 0.95]

1.1 Moderate 2 791 Odds Ratio (M-H, Fixed, 95% CI) 0.76 [0.55, 1.04]

1.2 Severe 6 474 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.58, 1.31]

1.3 Life threatening 7 478 Odds Ratio (M-H, Fixed, 95% CI) 0.69 [0.46, 1.03]

2 Hospital admissions (by

co-medications)

11 1769 Odds Ratio (M-H, Fixed, 95% CI) 0.75 [0.60, 0.92]

2.1 Nebulised ipratropium

bromide


2.2 No nebulised ipratropium

bromide


3 Hospital admissions (risk of bias

sensitivity)


4 Hospital admissions

(unpublished sensitivity)


5 PEF % predicted (Goodacre

change score sensitivity)

3 1129 Mean Difference (IV, Fixed, 95% CI) 1.57 [-0.55, 3.69]



6 PEF L/min (Goodacre change

score sensitivity)

8 1460 Mean Difference (IV, Fixed, 95% CI) 9.44 [2.07, 16.81]

Analysis 1.1. Comparison 1 IV MgSO4 versus placebo, Outcome 1 Hospital admissions.

Review: Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department

Comparison: 1 IV MgSO4 versus placebo

Outcome: 1 Hospital admissions

Study or subgroup Magnesium Placebo Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Bilaceroglu 2001 10/40 17/41 6.3 % 0.47 [ 0.18, 1.21 ]

Bloch 1995 17/67 24/68 8.9 % 0.62 [ 0.30, 1.31 ]

Boonyavorakul 2000 3/17 4/16 1.7 % 0.64 [ 0.12, 3.46 ]

Bradshaw 2007 49/62 52/67 5.3 % 1.09 [ 0.47, 2.52 ]

Goodacre 2013 279/394 278/358 42.6 % 0.70 [ 0.50, 0.97 ]

Green 1992 13/58 11/62 4.1 % 1.34 [ 0.55, 3.29 ]

Matusiewicz 1994 45/64 47/67 6.8 % 1.01 [ 0.48, 2.13 ]

Porter 2001 5/18 5/24 1.6 % 1.46 [ 0.35, 6.08 ]

Silverman 2002 39/122 41/126 13.8 % 0.97 [ 0.57, 1.66 ]

Singh 2008 2/30 9/30 4.2 % 0.17 [ 0.03, 0.85 ]

Skobeloff 1989 7/19 15/19 4.7 % 0.16 [ 0.04, 0.66 ]

Total (95% CI) 891 878 100.0 % 0.75 [ 0.60, 0.92 ]

Total events: 469 (Magnesium), 503 (Placebo)

Heterogeneity: Chi2 = 13.93, df = 10 (P = 0.18); I2 =28%

Test for overall effect: Z = 2.72 (P = 0.0066)

Test for subgroup differences: Not applicable

0.02 0.1 1 10 50

Favours Magnesium Favours Placebo



Analysis 1.2. Comparison 1 IV MgSO4 versus placebo, Outcome 2 Intensive care unit (ICU) admissions.



Outcome: 2 Intensive care unit (ICU) admissions

Study or subgroup Magnesium Placebo Odds Ratio Odds Ratio


Goodacre 2013 11/394 5/358 2.03 [ 0.70, 5.89 ]

0.01 0.1 1 10 100

Favours Placebo Favours Magnesium

Analysis 1.3. Comparison 1 IV MgSO4 versus placebo, Outcome 3 High dependency unit (HDU) admissions.



Outcome: 3 High dependency unit (HDU) admissions

Study or subgroup Magnesium Placebo Odds Ratio Odds Ratio


Goodacre 2013 23/394 20/358 1.05 [ 0.57, 1.94 ]

0.01 0.1 1 10 100




Analysis 1.4. Comparison 1 IV MgSO4 versus placebo, Outcome 4 ED treatment duration (minutes).



Outcome: 4 ED treatment duration (minutes)

Study or subgroup Magnesium PlaceboMean

DifferenceMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Green 1992 (1) 45 224 (75) 51 228 (90) -4.00 [ -37.02, 29.02 ]

-100 -50 0 50 100


(1) Reported only for those who were discharged (i.e. those not counted in hospital admissions)

Analysis 1.5. Comparison 1 IV MgSO4 versus placebo, Outcome 5 Length of hospital stay (days).



Outcome: 5 Length of hospital stay (days)


Difference WeightMean

Difference


Bilaceroglu 2001 (1) 23 5.7 (2.1) 23 6.1 (1.9) 6.7 % -0.40 [ -1.56, 0.76 ]

Bilaceroglu 2001 (2) 17 7.8 (2.3) 14 9.2 (2.3) 3.4 % -1.40 [ -3.03, 0.23 ]

Goodacre 2013 (3) 394 2.375 (3.129) 358 2.64 (3.5125) 39.6 % -0.26 [ -0.74, 0.21 ]

Green 1992 58 2.4 (1.5) 62 2.1 (0.7) 50.3 % 0.30 [ -0.12, 0.72 ]

Total (95% CI) 492 457 100.0 % -0.03 [ -0.33, 0.27 ]




-4 -2 0 2 4




(1) moderate

(2) severe

(3) Converted from hours to days

Analysis 1.6. Comparison 1 IV MgSO4 versus placebo, Outcome 6 Readmission.



Outcome: 6 Readmission



Bloch 1995 (1) 3/67 0/68 13.2 % 7.43 [ 0.38, 146.75 ]

Goodacre 2013 (2) 5/394 3/358 86.8 % 1.52 [ 0.36, 6.41 ]

Total (95% CI) 461 426 100.0 % 2.30 [ 0.66, 7.99 ]


Heterogeneity: Chi2 = 0.91, df = 1 (P = 0.34); I2 =0.0%



0.005 0.1 1 10 200


(1) within 1 week

(2) within 1 month



Analysis 1.7. Comparison 1 IV MgSO4 versus placebo, Outcome 7 Heart rate (bpm).



Outcome: 7 Heart rate (bpm)



Difference


Bloch 1995 (1) 67 102.5 (15.7) 68 99.9 (16.3) 10.6 % 2.60 [ -2.80, 8.00 ]

Goodacre 2013 (2) 394 105.7 (18.1) 358 105.9 (17.5) 47.8 % -0.20 [ -2.75, 2.35 ]

Silverman 2002 (3) 122 96 (15) 126 102 (15) 22.2 % -6.00 [ -9.73, -2.27 ]

Singh 2008 (4) 30 100 (7.43) 30 106.27 (8.34) 19.4 % -6.27 [ -10.27, -2.27 ]

Total (95% CI) 613 582 100.0 % -2.37 [ -4.13, -0.61 ]




-20 -10 0 10 20


(1) All groups

(2) at 120 mins

(3) at 240 mins

(4) at 120 mins



Analysis 1.8. Comparison 1 IV MgSO4 versus placebo, Outcome 8 Respiratory rate (breaths/min).



Outcome: 8 Respiratory rate (breaths/min)



Difference


Bloch 1995 (1) 67 18.9 (3.1) 68 20 (4.1) 15.7 % -1.10 [ -2.32, 0.12 ]

Goodacre 2013 (2) 394 20.6 (5.3) 358 21 (5.4) 40.1 % -0.40 [ -1.17, 0.37 ]

Silverman 2002 (3) 122 20 (4.1) 126 20 (4.1) 22.6 % 0.0 [ -1.02, 1.02 ]

Singh 2008 (4) 30 21.83 (1.55) 30 21.6 (2.46) 21.7 % 0.23 [ -0.81, 1.27 ]

Total (95% CI) 613 582 100.0 % -0.28 [ -0.77, 0.20 ]




-4 -2 0 2 4


(1) All groups at 120 mins

(2) at 120 mins

(3) at 240 mins

(4) at 120 mins



Analysis 1.9. Comparison 1 IV MgSO4 versus placebo, Outcome 9 Systolic blood pressure (mmHg).



Outcome: 9 Systolic blood pressure (mmHg)



Difference


Bloch 1995 (1) 67 122.7 (17.4) 68 126 (15.6) 12.5 % -3.30 [ -8.88, 2.28 ]

Bradshaw 2007 (2) 62 123.5 (33) 67 134.6 (33) 3.0 % -11.10 [ -22.50, 0.30 ]

Goodacre 2013 (3) 394 125.5 (16.5) 358 124.9 (18.5) 61.6 % 0.60 [ -1.92, 3.12 ]

Silverman 2002 (4) 122 123 (18) 126 121 (15) 22.8 % 2.00 [ -2.13, 6.13 ]

Total (95% CI) 645 619 100.0 % 0.08 [ -1.89, 2.05 ]




-20 -10 0 10 20



(2) All groups at 60 mins. SD estimated from p value.

(3) at 120 mins

(4) at 240 mins



Analysis 1.10. Comparison 1 IV MgSO4 versus placebo, Outcome 10 FEV1 (% predicted).



Outcome: 10 FEV1 (% predicted)



Difference


Bilaceroglu 2001 (1) 23 56.8 (19.2313) 23 57.15 (17.6007) 6.2 % -0.35 [ -11.00, 10.30 ]

Bilaceroglu 2001 (2) 17 62.34 (16.245) 17 52.66 (16.6161) 5.8 % 9.68 [ -1.37, 20.73 ]

Bloch 1995 (3) 67 55 (20.4634) 68 56 (20.6155) 14.7 % -1.00 [ -7.93, 5.93 ]

Silverman 2002 (4) 122 48.2 (18.1) 126 43.5 (18.7) 33.6 % 4.70 [ 0.12, 9.28 ]

Singh 2008 (5) 30 62.84 (10.02) 30 56.7 (6.2) 39.7 % 6.14 [ 1.92, 10.36 ]

Total (95% CI) 259 264 100.0 % 4.41 [ 1.75, 7.06 ]




-20 -10 0 10 20


(1) Moderate at 180 mins

(2) Severe at 180 mins

(3) All groups at 120 mins. SEM calculated from graph.

(4) at 240 mins

(5) at 120 mins



Analysis 1.11. Comparison 1 IV MgSO4 versus placebo, Outcome 11 PEF (% predicted).



Outcome: 11 PEF (% predicted)



Difference


Bradshaw 2007 (1) 62 65.4 (21.0197) 67 62.8 (21.0197) 13.3 % 2.60 [ -4.66, 9.86 ]

Goodacre 2013 (2) 394 68.6 (23.3) 358 65 (22.7) 64.7 % 3.60 [ 0.31, 6.89 ]

Silverman 2002 (3) 122 62.7 (24.3) 126 53.1 (20.9) 22.0 % 9.60 [ 3.95, 15.25 ]

Total (95% CI) 578 551 100.0 % 4.78 [ 2.14, 7.43 ]




-20 -10 0 10 20



(2) at 120 mins

(3) at 240 mins



Analysis 1.12. Comparison 1 IV MgSO4 versus placebo, Outcome 12 PEF (L/min).



Outcome: 12 PEF (L/min)



Difference


Bijani 2001 (1) 48 82.6 (40.1836) 33 47.8 (49.9777) 18.3 % 34.80 [ 14.31, 55.29 ]

Goodacre 2013 (2) 394 288.1 (111.2) 358 278.9 (105.5) 32.0 % 9.20 [ -6.29, 24.69 ]

Green 1992 (3) 58 263 (122) 62 278 (104) 4.6 % -15.00 [ -55.69, 25.69 ]

Matusiewicz 1994 (4) 64 279 (112) 67 256 (106.4096) 5.5 % 23.00 [ -14.45, 60.45 ]

Porter 2001 (5) 18 211 (104) 24 252 (108) 1.8 % -41.00 [ -105.62, 23.62 ]

Silverman 2002 (6) 122 272 (144) 126 236 (123) 6.9 % 36.00 [ 2.62, 69.38 ]

Skobeloff 1989 (7) 19 72 (80) 19 8 (80) 3.0 % 64.00 [ 13.13, 114.87 ]

Tiffany 1993 (8) 27 12.4 (27.5396) 21 -1.6 (30.245) 27.9 % 14.00 [ -2.59, 30.59 ]

Total (95% CI) 750 710 100.0 % 17.40 [ 8.64, 26.17 ]




-100 -50 0 50 100


(1) Mean change at 180 mins

(2) Endpoint at 120 mins

(3) Endpoint at ’final timepoint’




(7) Mean change at 45 mins. SD estimated from p value.

(8) Mean change at 20 mins. SD calculated from SEM



Analysis 1.13. Comparison 1 IV MgSO4 versus placebo, Outcome 13 Borg Dyspnoea Scale score.



Outcome: 13 Borg Dyspnoea Scale score



Difference


Bloch 1995 (1) 67 2.8 (1.9) 68 3 (2.2) -0.20 [ -0.89, 0.49 ]

Porter 2001 (2) 18 2.2 (4.65) 24 1.6 (4.65) 0.60 [ -2.24, 3.44 ]

Silverman 2002 (3) 122 1.9 (2.1) 126 2 (2.1) -0.10 [ -0.62, 0.42 ]

Singh 2008 (4) 30 2 (0.83) 30 2.4 (1.35) -0.40 [ -0.97, 0.17 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)


-4 -2 0 2 4


(1) Borg Dyspnoea Scale at 120 mins

(2) Borg Dyspnoea Scale at 60 mins; SDs estimated from exact p-value





Analysis 2.1. Comparison 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses), Outcome 1

Hospital admissions (by severity).


Comparison: 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses)

Outcome: 1 Hospital admissions (by severity)



1 Moderate

Bradshaw 2007 16/20 11/19 1.2 % 2.91 [ 0.70, 12.09 ]

Goodacre 2013 279/394 278/358 43.6 % 0.70 [ 0.50, 0.97 ]

Subtotal (95% CI) 414 377 44.8 % 0.76 [ 0.55, 1.04 ]




2 Severe

Bilaceroglu 2001 (1) 4/23 8/27 3.1 % 0.50 [ 0.13, 1.94 ]

Bloch 1995 10/25 11/49 2.3 % 2.30 [ 0.81, 6.54 ]

Bradshaw 2007 21/30 26/31 3.9 % 0.45 [ 0.13, 1.54 ]

Green 1992 13/58 11/62 4.2 % 1.34 [ 0.55, 3.29 ]

Matusiewicz 1994 45/64 47/67 7.0 % 1.01 [ 0.48, 2.13 ]

Skobeloff 1989 7/19 15/19 4.9 % 0.16 [ 0.04, 0.66 ]

Subtotal (95% CI) 219 255 25.4 % 0.87 [ 0.58, 1.31 ]




3 Life threatening

Bilaceroglu 2001 (2) 6/17 9/14 3.3 % 0.30 [ 0.07, 1.33 ]

Bloch 1995 7/21 11/14 4.5 % 0.14 [ 0.03, 0.65 ]

Boonyavorakul 2000 3/17 4/16 1.7 % 0.64 [ 0.12, 3.46 ]

Bradshaw 2007 12/12 15/17 0.3 % 4.03 [ 0.18, 91.91 ]

Porter 2001 5/18 5/24 1.6 % 1.46 [ 0.35, 6.08 ]

Silverman 2002 39/122 41/126 14.1 % 0.97 [ 0.57, 1.66 ]

Singh 2008 2/30 9/30 4.3 % 0.17 [ 0.03, 0.85 ]

Subtotal (95% CI) 237 241 29.8 % 0.69 [ 0.46, 1.03 ]



0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Magnesium Placebo Odds Ratio Weight Odds Ratio



Total (95% CI) 870 873 100.0 % 0.76 [ 0.62, 0.95 ]




Test for subgroup differences: Chi2 = 0.63, df = 2 (P = 0.73), I2 =0.0%

0.01 0.1 1 10 100


(1) Moderate

(2) Severe


Hospital admissions (by co-medications).



Outcome: 2 Hospital admissions (by co-medications)



1 Nebulised ipratropium bromide

Bradshaw 2007 (1) 49/62 52/67 5.3 % 1.09 [ 0.47, 2.52 ]

Goodacre 2013 279/394 278/358 42.6 % 0.70 [ 0.50, 0.97 ]

Matusiewicz 1994 45/64 47/67 6.8 % 1.01 [ 0.48, 2.13 ]

Singh 2008 2/30 9/30 4.2 % 0.17 [ 0.03, 0.85 ]

Subtotal (95% CI) 550 522 58.9 % 0.73 [ 0.55, 0.96 ]




2 No nebulised ipratropium bromide

Bilaceroglu 2001 (2) 10/40 17/41 6.3 % 0.47 [ 0.18, 1.21 ]

Bloch 1995 (3) 17/67 24/68 8.9 % 0.62 [ 0.30, 1.31 ]

0.02 0.1 1 10 50


(Continued . . . )



(. . . Continued)Study or subgroup Magnesium Placebo Odds Ratio Weight Odds Ratio


Boonyavorakul 2000 3/17 4/16 1.7 % 0.64 [ 0.12, 3.46 ]

Green 1992 13/58 11/62 4.1 % 1.34 [ 0.55, 3.29 ]

Porter 2001 5/18 5/24 1.6 % 1.46 [ 0.35, 6.08 ]

Silverman 2002 39/122 41/126 13.8 % 0.97 [ 0.57, 1.66 ]

Skobeloff 1989 7/19 15/19 4.7 % 0.16 [ 0.04, 0.66 ]

Subtotal (95% CI) 341 356 41.1 % 0.77 [ 0.55, 1.06 ]




Total (95% CI) 891 878 100.0 % 0.75 [ 0.60, 0.92 ]




Test for subgroup differences: Chi2 = 0.05, df = 1 (P = 0.82), I2 =0.0%

0.02 0.1 1 10 50


(1) All groups

(2) Moderate

(3) All groups




Hospital admissions (risk of bias sensitivity).



Outcome: 3 Hospital admissions (risk of bias sensitivity)



Bloch 1995 (1) 17/67 24/68 10.8 % 0.62 [ 0.30, 1.31 ]

Boonyavorakul 2000 3/17 4/16 2.1 % 0.64 [ 0.12, 3.46 ]

Bradshaw 2007 (2) 49/62 52/67 6.3 % 1.09 [ 0.47, 2.52 ]

Goodacre 2013 279/394 278/358 51.5 % 0.70 [ 0.50, 0.97 ]

Porter 2001 5/18 5/24 1.9 % 1.46 [ 0.35, 6.08 ]

Silverman 2002 39/122 41/126 16.6 % 0.97 [ 0.57, 1.66 ]

Singh 2008 2/30 9/30 5.1 % 0.17 [ 0.03, 0.85 ]

Skobeloff 1989 7/19 15/19 5.7 % 0.16 [ 0.04, 0.66 ]

Total (95% CI) 729 708 100.0 % 0.72 [ 0.57, 0.91 ]





0.01 0.1 1 10 100


(1) All groups

(2) All groups




Hospital admissions (unpublished sensitivity).



Outcome: 4 Hospital admissions (unpublished sensitivity)



Bilaceroglu 2001 (1) 10/40 17/41 6.8 % 0.47 [ 0.18, 1.21 ]

Bloch 1995 (2) 17/67 24/68 9.6 % 0.62 [ 0.30, 1.31 ]

Boonyavorakul 2000 3/17 4/16 1.8 % 0.64 [ 0.12, 3.46 ]

Bradshaw 2007 (3) 49/62 52/67 5.6 % 1.09 [ 0.47, 2.52 ]

Goodacre 2013 279/394 278/358 45.7 % 0.70 [ 0.50, 0.97 ]

Green 1992 13/58 11/62 4.4 % 1.34 [ 0.55, 3.29 ]

Porter 2001 5/18 5/24 1.7 % 1.46 [ 0.35, 6.08 ]

Silverman 2002 39/122 41/126 14.8 % 0.97 [ 0.57, 1.66 ]

Singh 2008 2/30 9/30 4.5 % 0.17 [ 0.03, 0.85 ]

Skobeloff 1989 7/19 15/19 5.1 % 0.16 [ 0.04, 0.66 ]

Total (95% CI) 827 811 100.0 % 0.73 [ 0.58, 0.91 ]





0.01 0.1 1 10 100


(1) Severe

(2) All groups

(3) All groups



Analysis 2.5. Comparison 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses), Outcome 5 PEF

% predicted (Goodacre change score sensitivity).



Outcome: 5 PEF % predicted (Goodacre change score sensitivity)



Difference


Bradshaw 2007 (1) 62 65.4 (21.0197) 67 62.8 (21.0197) 8.5 % 2.60 [ -4.66, 9.86 ]

Goodacre 2013 (2) 394 14.4 (17.4) 358 14.4 (16.3) 77.4 % 0.0 [ -2.41, 2.41 ]

Silverman 2002 (3) 122 62.7 (24.3) 126 53.1 (20.9) 14.1 % 9.60 [ 3.95, 15.25 ]

Total (95% CI) 578 551 100.0 % 1.57 [ -0.55, 3.69 ]




-20 -10 0 10 20



(2) at 120 mins

(3) at 240 mins



Analysis 2.6. Comparison 2 IV MgSO4 versus placebo (subgroup and sensitivity analyses), Outcome 6 PEF

L/min (Goodacre change score sensitivity).



Outcome: 6 PEF L/min (Goodacre change score sensitivity)



Difference


Bijani 2001 (1) 48 82.6 (40.1836) 33 47.8 (49.9777) 12.9 % 34.80 [ 14.31, 55.29 ]

Goodacre 2013 (2) 394 61 (73.6) 358 62.5 (69.4) 51.9 % -1.50 [ -11.72, 8.72 ]

Green 1992 (3) 58 263 (122) 62 278 (104) 3.3 % -15.00 [ -55.69, 25.69 ]

Matusiewicz 1994 (4) 64 279 (112) 67 256 (106.4096) 3.9 % 23.00 [ -14.45, 60.45 ]

Porter 2001 (5) 18 211 (104) 24 252 (108) 1.3 % -41.00 [ -105.62, 23.62 ]

Silverman 2002 (6) 122 272 (144) 126 236 (123) 4.9 % 36.00 [ 2.62, 69.38 ]

Skobeloff 1989 (7) 19 72 (80) 19 8 (80) 2.1 % 64.00 [ 13.13, 114.87 ]

Tiffany 1993 (8) 27 12.4 (27.5396) 21 -1.6 (30.245) 19.7 % 14.00 [ -2.59, 30.59 ]

Total (95% CI) 750 710 100.0 % 9.44 [ 2.07, 16.81 ]




-100 -50 0 50 100


(1) Mean change at 180 mins


(3) Endpoint at ’final timepoint’




(7) Mean change at 45 mins. SD estimated from p value.

(8) Mean change at 20 mins. SD calculated from SEM



A D D I T I O N A L T A B L E S

Table 1. Summary of guideline treatment recommendations in acute asthma (adults)

BTS/SIGN GINA NACA NAEPP

Oxygen√ √ √ √

Inhaled beta2-agonist√ √ √ √

Inhaled antimuscarinic√ √ √ √

Sytemic corticosteroids√ √ √ √

IV beta2-agonist (√

)

if nebulised form cannot

be used

reliably

x√

if no response to inhaled

form

x

IV MgSO4√ √ √

IV or nebulised

√

Heliox x x x√

IV aminophylline/

theophylline

(√

)

limited evidence, only

after senior consultation

(√

)

if inhaled beta2-agonist

unavailable

(√

)

as an alternative to IV

beta2-agonist

x

BTS/SIGN: British Thoracic Society and Scottish Intercollegiate Guidelines Network joint guideline; GINA: Global Initiative for

Asthma; IV: Intravenous; NACA: National Asthma Council Australia; NAEPP: National Asthma Education and Prevention Program;√: Recommended; x: Not recommended; (

√): Recommended with conditions.

Table 2. Summary characteristics of included studies

Study ID Country (cen-

tres)

Total N Study design Age range (years) Dose (infusion) Co-medications

Bijani 2001 Iran 81 R, DB, PC 12-85 25 mg/kg (30 min-

utes)

Nebulised SABA, IV

xanthine, IV corti-

costeroid, O2

Bilaceroglu 2001 Turkey 81 R, SB, PC 6-65 1 g or 2 g (unclear) O2 (if PaO2 was < 60

mmHg)

Bloch 1995 USA (2) 149 R, DB, PC 18-65 2 g (20 minutes) Nebulised SABA, IV

corticosteroid

Boonyavorakul

2000

Thailand (1) 34 R, DB, PC 15-65 2 g (unclear) Nebulised SABA, IV

corticosteroid, O2 if

necessary



Table 2. Summary characteristics of included studies (Continued)

Bradshaw 2007 Scotland (1) 129 R, DB, PC 16+ 1.2 g (15 minutes) Nebulised SABA,

nebulised LAMA, IV

corticosteroid, O2

Del Castillo

Rueda 1991

Spain (1) 16 R, DB, PC ? 1.5 g (15 minutes) Nebulised SABA, IV

corticosteroid

Goodacre 2013 UK (34) 1109 R, DB, PC 16+ 2 g (20 minutes) Nebulised SABA and

LAMA, oral corticos-

teroid, O2

Green 1992 USA (1) 137 ? 18-65 2 g (20 minutes) Nebulised SABA, IV

corticosteroid (others

at physician’s discre-

tion), O2

Matusiewicz

1994

UK (1) 131 R Adults 1.2 g (15 minutes) Nebulised SABA and

LAMA, O2, IV corti-

costeroid (discre-

tionary xanthine)

Porter 2001 USA (1) 42 R, DB, PC 18-55 2 g (unclear) Nebulised SABA, IV

corticosteroid, O2

Silverman 2002 USA (8) 248 R, DB, PC 18-60 2 g (15 minutes) Nebulised SABA, IV

corticosteroid, O2

Singh 2008 India (1) 70 R, SB, PC 18-60 2 g (20 minutes) Nebulised SABA,

nebulised LAMA, IV

corticosteroid, O2

Skobeloff 1989 USA (1) 38 R, DB, PC 18-70 1.2 g (20 minutes) Nebulised SABA, IV

metaproterenol, IV

xanthine

Tiffany 1993 USA (1) 48 R, DB, PC 18-60 2 g (20 minutes) Nebulised SABA, IV

corticosteroid, SABA

aerosol, IV xanthine

DB: Double-blind; IV: Intravenous; LAMA: Long-acting muscarinic antagonist; O2: Oxygen; PaO2: Partial pressure of oxygen in

arterial blood; PC: Placebo-controlled; R: Randomised; SABA: Short-acting beta2-agonist; SB: Single-blind.

Bilaceroglu 2001 included adults and children, but only 10 participants were younger than 18 years of age; mean age was 36 (± 13.4)

years.



Table 3. Baseline severity criteria

Study ID Inclusion Category

within trial

PEF FEV1 Other Classification*

Bijani 2001 PEF < 200 af-

ter bronchodila-

tor and corticos-

teroids

All participants 31% predicted - RR = 35 rpm Life threatening

Bilaceroglu 2001 PEF increasing <

50% or

FEV1

< 75% predicted

after single

salbutamol

Moderate 57% predicted 43% predicted PaO2 = 69

mmHg

Severe

Severe 32% predicted 32% predicted PaO2 = 64

mmHg

Life threatening

Bloch 1995 FEV1

< 75% predicted

after single

salbutamol

Moderate - 40% predicted - Severe

Severe - 20% predicted - Life threatening

Boonyavorakul

2000

Composite

severity score

All participants - - RR = 33 rpm

HR = 125 bpm

Life threatening

Bradshaw 2007 PEF < 75% pre-

dicted

Moderate 60% predicted

248 L/min

- HR = 102 bpm Moderate

Severe 41% predicted

170 L/min

- HR = 109 bpm Severe

Life threatening 23% predicted

96 L/min

- HR = 116 bpm Life threatening

Del Castillo

Rueda 1991

- All participants - - - Unknown (not in

analysis)

Goodacre 2013 One or more

of the following:

PEF < 50% pre-

dicted; RR > 25,

HR > 110

or cannot com-

plete sen-

tences, but not

life threatening

All participants 52% predicted

433 L/min

- - Moderate

Green 1992 - All participants 143 L/min - RR = 29 rpm

HR = 108 bpm

Severe



Table 3. Baseline severity criteria (Continued)

Matusiewicz

1994

PEF < 250 L/

min or < 50%

predicted

All participants - - - Severe

Porter 2001 PEF < 100 L/

min or < 25%

predicted

All participants 88.5 L/min - RR = 31 rpm

HR = 110 bpm

Life threatening

Silverman 2002 FEV1 < 30%

predicted

All participants 27% predicted

143 L/min

23% predicted HR = 102 bpm Life threatening

Singh 2008 FEV1 < 30%

predicted

All participants 22% predicted 38% predicted HR = 127 bpm Life threatening

Skobeloff 1989 PEF < 200 L/

min, not dou-

bled after beta-

agonist, IV cor-

ticosteroid, theo-

phylline

All participants ~150 L/min

(from graph)

- HR = ~ 100 bpm

from graph

RR = ~ 28

Severe

Tiffany 1993 PEF

< 200 L/min, not

doubled after al-

buterol × 2

All participants 115 L/min 0.95 L - Life threatening

bpm: Beats per minute; FEV1: Forced expiratory volume in 1 second; HR: Heart rate; PaO2: Partial pressure of oxygen in arterial

blood; PEF: Peak expiratory flow; rpm: Respirations per minute;RR: Respiration rate..

Classification for the severity subgroup analysis was assigned by an independent clinician and was cross-checked with study authors’

own judgements. Discrepancies were resolved through discussion.



A P P E N D I C E S

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register(CAGR)

Electronic searches: core databases

Database Frequency of search

CENTRAL (The Cochrane Library) Monthly

MEDLINE (Ovid) Weekly

EMBASE (Ovid) Weekly

PsycINFO (Ovid) Monthly

CINAHL (EBSCO) Monthly

AMED (EBSCO) Monthly

Handsearches: core respiratory conference abstracts

Conference Years searched

American Academy of Allergy, Asthma and Immunology (AAAAI) 2001 onwards

American Thoracic Society (ATS) 2001 onwards

Asia Pacific Society of Respirology (APSR) 2004 onwards

British Thoracic Society Winter Meeting (BTS) 2000 onwards

Chest Meeting 2003 onwards

European Respiratory Society (ERS) 1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG) 2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ) 1999 onwards



MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

Filter to identify RCTs

1. exp “clinical trial [publication type]”/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

Appendix 2. Search strategy to identify relevant trials from the CAGR

#1 AST:MISC1

#2 MeSH DESCRIPTOR Asthma Explode All

#3 asthma*:ti,ab

#4 #1 or #2 or #3

#5 magnesium*

#6 MgSO4

#7 #5 or #6

#8 #4 and #7

#9 (#8) AND (INREGISTER)

[Note: in search line #1, MISC1 refers to the field in which the reference record has been coded for condition, in this case, asthma]



C O N T R I B U T I O N S O F A U T H O R S

All review authors contributed to all aspects of the review.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

• No sources of support supplied

External sources

• KK, UK.

National Institute for Health Research (NIHR). Programme grant funding

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We could not carry out the prespecified subgroup analysis based on age, as no studies had a mean participant age above 65 years. For

the severity subgroup analysis, we renamed the categories from mild, moderate and severe to moderate, severe and life threatening to fit

with BTS/SIGN 2012 classifications. For the co-medications subgroup analysis, we changed the labelling from ’maximal and minimal’

to ’with and without ipratropium bromide’ so as not to imply preference of one strategy over the other (definitions remained the same).

We considered a meta-analysis of O2 saturations to be not viable. We added a post-hoc sensitivity analysis using change from baseline

instead of endpoint means from Goodacre 2013, as baseline imbalances were noted in this study.



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